Oxazole compounds for the treatment of neurodegenerative disorders

ABSTRACT

The present invention relates to compounds of the Formula  
                 
 
wherein R 3 , R 5 , R 6 , R 7 , and Z, and other variables enumerated under one or more of R 3 , R 5 , R 6 , R 7 , and Z, are as defined. Compounds of the Formula I have activity inhibiting production of Aβ-peptide. This invention also relates to pharmaceutical compositions and methods of treating diseases, for example, neurodegenerative diseases, e.g., Alzheimer&#39;s disease, in a mammal comprising compounds of the Formula I.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a continuation-in-part of pending U.S.provisional application No. 60/498,028 filed Aug. 27, 2003, which is acontinuation-in-part of pending U.S. provisional application No.60/492,884 filed Aug. 6, 2003.

FIELD OF THE INVENTION

The present invention relates to the treatment of Alzheimer's diseaseand other neurodegenerative and/or neurological disorders in mammals,including humans. This invention also relates to inhibiting, in mammals,including humans, the production of Aβ-peptides that can contribute tothe formation of neurological deposits of amyloid protein. Moreparticularly, this invention relates to oxazole compounds useful for thetreatment of neurodegenerative and/or neurological disorders, such asAlzheimer's disease and Down's Syndrome, related to Aβ-peptideproduction.

BACKGROUND OF THE INVENTION

Dementia results from a wide variety of distinctive pathologicalprocesses. The most common pathological processes causing dementia areAlzheimer's disease (AD), cerebral amyloid angiopathy (CM) andprion-mediated diseases (see, e.g., Haan et al. Clin. NeuroL Neurosurg.1990, 92(4):305-310; Glenner et al. J Neurol. Sci. 1989, 94:1-28). ADaffects nearly half of all people past the age of 85, the most rapidlygrowing portion of the United States population. As such, the number ofAD patients in the United States is expected to increase from about 4million to about 14 million by the middle of the next century.

Treatment of AD typically is the support provided by a family member inattendance. Stimulated memory exercises on a regular basis have beenshown to slow, but not stop, memory loss. A few drugs, for exampleAricep™, provide treatment of AD.

A hallmark of AD is the accumulation in the brain of extracellularinsoluble deposits called amyloid plaques and abnormal lesions withinneuronal cells called neurofibrillary tangles. Increased plaqueformation is associated with an increased risk of AD. Indeed, thepresence of amyloid plaques, together with neurofibrillary tangles, arethe basis for definitive pathological diagnosis of AD.

The major components of amyloid plaques are the amyloid Aβ-peptides,also called Aβ-peptides, which consist of three proteins having 40, 42or 43 amino acids, designated as the Aβ₁₋₄₀, Aβ₁₋₄₂, and Aβ₁₋₄₃peptides, respectively. The Aβ-peptides are thought to cause nerve celldestruction, in part, because they are toxic to neurons in vitro and invivo.

The Aβ peptides are derived from larger amyloid precursor proteins (APPproteins), which consist of four proteins containing 695, 714, 751 or771 amino acids, designated as the APP₆₉₅, APP₇₁₄, APP₇₅₁ and APP₇₇₁,respectively. Proteases are believed to produce the Aβ peptides bycleaving specific amino acid sequences within the various APP proteins.The proteases are named “secretases” because the Aβ-peptides theyproduce are secreted by cells into the extracellular environment. Thesesecretases are each named according to the cleavage(s) they make toproduce the Aβ-peptides. The secretase that forms the amino terminal endof the Aβ-peptides is called the beta-secretase. The secretase thatforms the carboxyl terminal end of the Aβ-peptides is called thegamma-secretase (Haass, C. and Selkoe, D. J. 1993 Cell 75:1039-1042).

This invention relates to novel compounds that inhibit Aβ-peptideproduction, to pharmaceutical compositions comprising such compounds,and to methods of using such compounds to treat neuorodegenerativeand/or neurological disorders.

SUMMARY OF THE INVENTION

The present invention relates to compounds of the formula

wherein Z is selected from —C(═O)CHR¹R², —C(═S)CHR¹R², —(C═NR⁸)CHR¹R²,—C(═O)C(═O)R¹ and —S(O)₂—R¹;

R¹ is selected from -C₁-C₂₀ alkyl, -C₂-C₂₀ alkenyl, -C₂-C₂₀ alkynyl,-C₁-C₂₀ alkoxy, -C₂-C₂₀ alkenoxy, -C₂-C₂₀ alkynoxy, -C₃-C₂₀ cycloalkyl,-C₄-C₂₀ cycloalkenyl, (C₁₀-C₂₀)bi- or tricycloalkyl, (C₁₀-C₂₀)bi- ortricycloalkenyl, (4-20 membered) heterocycloalkyl, -C₆-C₂₀ aryl and(5-20 membered) heteroaryl;

wherein R¹ is optionally independently substituted with from one to sixfluorine atoms or with from one to three substituents independentlyselected from the group R^(1a);

R^(1a) is in each instance independently selected from —OH, -C₁-C₁₂alkyl, -C₂-C₁₂ alkenyl, -C₂-C₁₂ alkynyl, -C₁-C₆ alkoxy, -C₂-C₆ alkenoxy,-C₂-C₆ alkynoxy, —F, —Cl, —Br, —I, —CN, —NO₂, —NR⁹R¹⁰, —C(═O)NR⁹R¹⁰,—S(O)_(n)—NR⁹R¹⁰, —C(═O)R¹¹, —S(O)_(n)—R¹¹, —C(═O)OR¹², C₃-C₁₅cycloalkyl, -C₄-C₁₅ cycloalkenyl, -(C₅-C₁₁)bi- or tricycloalkyl,-(C₇-C₁₁)bi- or tricycloalkenyl, -(4-20 membered) heterocycloalkyl,-C₆-C₁₅ aryl, -(5-15 membered) heteroaryl, -C₆-C₁₅ aryloxy and -(5-15membered) heteroaryloxy, wherein said cycloalkyl, cycloalkenyl, bi- ortricycloalkyl, bi- or tricycloalkenyl, heterocycloalkyl, aryl,heteroaryl, aryloxy and heteroaryloxy are each optionally independentlysubstituted with from one to three substituents independently selectedfrom the group R^(1b);

R^(1b) is in each instance independently selected from —OH, -C₁-C₆alkyl, -C₂-C₆ alkenyl, -C₂-C₆ alkynyl, -C₁-C₆ alkoxy, -C₂-C₆ alkenoxy,-C₂-C₆ alkynoxy, -C₁-C₆ hydroxyalkyl, —F, —Cl, —Br, —I, —CN, —NO₂,—NR⁹R¹⁰, —C(═O)NR⁹R¹⁰, —C(═O)R¹¹, —S(O)_(n)NR⁹R¹⁰, —S(O)_(n)—R¹¹,-C₆-C₁₅ aryloxy and -(5-15 membered) heteroaryloxy, wherein said alkyl,alkenyl and alkynyl are each optionally independently substituted withfrom one to six fluorine atoms or with from one to two substituentsindependently selected from -C₁-C₄ alkoxy, or with a hydroxy group;

R⁹ and R¹⁰ are in each instance each independently selected from —H,-C₁-C₁₂ alkyl, -C₂-C₁₂ alkenyl, -C₂-C₁₂ alkynyl, —CF₃, —C(═O)R¹¹,—S(O)_(n)—R¹¹, —C(═O)OR¹², —C(═O)N R¹¹R¹², —S(O)_(n)—NR¹¹R¹²,-(C_(zero)-C₄ alkylene)-(C₃-C₂ cycloalkyl), -(C_(zero)-C₄alkylene)-(C₄-C₈ cycloalkenyl), -(C_(zero)-C₄ alkylene)-((C₅-C₁l)bi- ortricycloalkyl), -(C_(zero)-C₄alkylene)-((C₇-C₁₁)bi- or tricycloalkenyl),-(C_(zero)-C₄ alkylene)-((5-10 membered) heterocycloalkyl), (C_(zero)-C₄alkylene)-(C₆-C₁₀ aryl) and -(C_(zero)-C₄ alkylene)-((5-10 membered)heteroaryl), wherein said alkyl, alkenyl and alkynyl are each optionallyindependently substituted with from one to six fluorine atoms or withfrom one to two substituents independently selected from -C₁-C₄ alkoxy,or with a hydroxy group, and wherein said cycloalkyl, cycloalkenyl,bi-or tricycloalkyl, bi- or tricycloalkenyl, heterocycloalkyl, aryl andheteroaryl are each optionally independently substituted with from oneto three substituents independently selected from —OH, -C₁-C₁₂ alkyl,-C₂-C₁₂ alkenyl, -C₂-C₁₂ alkynyl, -C₁-C₆ alkoxy, -C₂-C₆ alkenoxy, -C₂-C₆alkynoxy, -C₁-C₆ hydroxyalkyl, —F, —Cl, —Br, —I, —CN, —NO₂, —CF₃, —NH₂,—C(═O)NH₂, —S(O)_(n)—NH₂, —C(═O)H and —C(═O)OH, wherein said alkyl,alkenyl and alkynyl substituents are each optionally independentlyfurther substituted with from one to six fluorine atoms or with from oneto two substituents independently selected from -C₁-C₄ alkoxy, or with ahydroxy group;

or NR⁹R¹⁰ may in each instance independently optionally form aheterocycloalkyl moiety of from four to ten ring members, saidheterocycloalkyl moiety optionally containing one to two furtherheteroatoms independently selected from N, O and S, and optionallycontaining from one to three double bonds, wherein the carbon atoms ofthe heterocycloalkyl moiety of NR⁹R¹⁰ are optionally independentlysubstituted with from one to three substituents independently selectedfrom —OH, -C₁-C₁₂ alkyl, -C₂-C₁₂alkenyl, -C₂-C₁₂ alkynyl, -C₁-C₆ alkoxy,-C₂-C₆ alkenoxy, -C₂-C₆ alkynoxy, —F, —Cl, —Br, —I, —CF₃, —NH₂,—C(═O)NH₂, —S(O)_(n)—NH₂, —C(═O)R¹¹, —S(O)_(n)—R¹¹, (C_(zero)-C₄alkylene)-(C₆-C₁₀ aryl), (C_(zero)-C₄ alkylene)-((5-10 memberedheteroaryl), (C_(zero)-C₄ alkylene)-(C₆-C₁₀ cycloalkyl) and (C_(zero)-C₄alkylene)-((5-10 membered) heterocycloalkyl, and wherein the(C_(zero)-C₄ alkylene)-((5-10 membered) heterocycloalkyl) substituentand the nitrogen atoms of said heterocycloalkyl moiety of NR⁹R¹⁰ areeach optionally independently substituted with one substituentindependently selected from -C₁-C₁₂ alkyl, -C₂-C₁₂ alkenyl, -C₂-C₁₂alkynyl, —C(═O)NH₂, —S(O)_(n)—NH₂, C(═O)R¹¹, —S(O)_(n)—R¹¹, (C_(zero)-C₄alkylene)-(C₆-C₁₀ aryl), (C_(zero)-C₄ alkylene)-((5-10 membered)heteroaryl), (C_(zero)-C₄ alkylene)-(C₆-C₁₀ cycloalkyl) and (C_(zero)-C₄alkylene)-((5-10 membered) heterocycloalkyl), and wherein said alkyl,alkenyl and alkynyl substituents are each optionally independentlyfurther substituted with from one to six fluorine atoms, or with fromone to two substituents independently selected from -C₁-C₄ alkoxy, orwith a hydroxy group;

R¹¹ and R¹² are in each instance each independently selected from-C₁-C₁₅ alkyl (branched or straight chain), -C₂-C₆ alkenyl, -C₂-C₆alkynyl, -(C_(zero)-C₄ alkylene)-(C₃-C₁₅ cycloalkyl), -(C_(zero)-C₄alkylene)-(C₄-C₈ cycloalkenyl), -(C_(zero)-C₄ alkylene)-((C₅-C₁₁)bi- ortricycloalkyl), -(C_(zero)-C₄ alkylene)-((C₇-C₁₁)bi- ortricycloalkenyl), -(C_(zero)-C₄ alkylene)-(C₆-C₁₅ aryl), -(C_(zero)-C₄alkylene)-((5-15 membered) heterocycloalkyl) and -(C_(zero)-C₄alkylene)-((5-15 membered) heteroaryl);

wherein R¹¹ and R¹² are each optionally independently substituted withfrom one to six fluorine atoms or with from one to three substituentsindependently selected from group R^(1b), and wherein said alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bi-or trcycloalkyl, bi- ortricycloalkenyl, heterocycloalkyl, aryl and heteroaryl are eachoptionally independently substituted with from one to three substituentsindependently selected from —OH, -C₁-C₁₂ alkyl, -C₂-C₁₂ alkenyl, -C₂-C₁₂alkynyl, -C₁-C₆ alkoxy, -C₂-C₆ alkenoxy, -C₂-C₆ alkynoxy, -C₁-C₆hydroxyalkyl, —F, —Cl, —Br, —I, —CN, —NO₂, —CF₃, —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆alkyl)₂, —NR⁹R¹⁰, —C(═O)NR⁹R¹⁰, —C(═O)R¹¹, —S(O)_(n)NR⁹R¹⁰,—S(O)_(n)—R¹¹, -C₆-C₁₅ aryloxy and -(5-15 membered) heteroaryloxy,—SO₂NH₂, —SO₂NH(C₁-C₆ alkyl), —SO₂N(C₁-C₆ alkyl)₂, —C(═O)H, —C(═O)OH and—C(═O)O(C₁-C₆ alkyl), wherein said alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkynyl substituents are each optionally independently furthersubstituted with from one to six fluorine atoms or with from one to twosubstituents independently selected from -C₁-C₄ alkoxy, or with ahydroxy group;

NR¹¹R¹² may in each instance independently optionally form aheterocycloalkyl moiety of from four to ten ring members, saidheterocycloalkyl moiety optionally containing one to two furtherheteroatoms independently selected from N, O and S, and optionallycontaining from one to three double bonds, wherein the carbon atoms ofsaid heterocycloalkyl moiety of NR⁹R¹⁰ are optionally independentlysubstituted with from one to three substituents independently selectedfrom —OH, -C₁-C,₂ alkyl, -C₂-C₁₂ alkenyl, -C₂-C₁₂ alkynyl, -C₁-C₆alkoxy, -C₂-C₆ alkenoxy, -C₂-C₆ alkynoxy, -C₁-C₆ hydroxyalkyl, —F, —Cl,—Br, —I, —CN, —NO₂, —CF₃, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂,—C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, —SO₂NH₂,—SO₂NH(C₁-C₆ alkyl), —SO₂N(C₁-C₆ alkyl)₂, —C(═O)H, —C(═O)OH and—C(═O)O(C₁-C₆ alkyl), wherein said alkyl, alkenyl and alkynylsubstituents are each optionally independently further substituted withfrom one to six fluorine atoms or with from one to two substituentsindependently selected from -C₁-C₄ alkoxy, or with a hydroxy group;

R² is selected from —H, —OH, —NH₂, —CH₂OH, —OC(═O)CH₃, —C(CH₃)₂OH,—C(CH₃)(CH₂CH₃)(OH), —C(OH)(C_(zero)-C₄ alkyl)(C_(zero)-C₄ alkyl),—OC(═O)R⁴ and —OC(═O)OR⁴, wherein said —OC(═O)R⁴ and —OC(═O)OR⁴ mayoptionally be a prodrug of the corresponding OH of R²;

R⁴ is selected from -C₁-C₄ alkyl, -CH(OH)(C₁-C₄ alkyl), -CH(OH)(C₅-C₆aryl), —CH(OH)((5-6 membered) heteroaryl), —CH(OH)(C₅-C₆ cycloalkyl),—CH(OH)((5-6 membered) heterocycloalkyl);

R³ is selected from -C₁-C₆ alkyl, -C₂-C₆ alkenyl, -C₂-C₆ alkynyl andC_(zero)-C₄ alkylene)-(C₃-C₆ cycloalkyl), wherein when R³ is alkyl,alkenyl, allyl, or alkynyl, R³ is optionally independently substitutedwith a substituent independently selected from -C₁-C₄ alkoxy, —OH and—S(C₁-C₄ alkyl);

R⁵ is selected from —H, -C₁-C₄ alkyl, -C₂-C₄ alkenyl, -C₂-C₄ alkynyl,—C(═O)(C₁-C₄ alkyl), -C₆-C₁₀ aryl, -(5-20 membered) heteroaryl,—S(O)_(n)-(C₆-C₁₀ aryl), —S(O)_(n)—((5-20 membered) heteroaryl),—S(O)_(n)—CH₂-(C₆-C₂₀ aryl) and —S(O)_(n)-CH₂-((5-20 membered)heteroaryl);

R⁶ is selected from —H, -C₁-C₄ alkyl, -C₂-C₄ alkenyl, -C₂-C₄ alkynyl,—F, —Cl, —Br, —I, —CN, —CF₃, —C(═O)NR⁹R¹⁰, —S(O)_(n)—NR⁹R¹⁰, —C(═O)R¹¹,—S(O)_(n)—R¹¹, —C(═O)OR¹², (C_(zero)-C₄ alkylene)-C(═O)OR¹², -C₃-C₂₀cycloalkyl, -C₄-C₂₀ cycloalkenyl and -C₆-C₁₀ aryl, wherein said alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl and aryl are each optionallyindependently substituted with from one to three substituentsindependently selected from the group R^(1b);

R⁷ is selected from —H, -C₁-C₂₀ alkyl, -C₂-C₂₀ alkenyl, -C₂-C₂₀alkynyl,-C₁-C₂₀ alkoxy, -C₂-C₂₀ alkenoxy, -C₂-C₂₀ alkynoxy, F, —Cl, —Br, —I,—CN, —NO₂, —OH, —CF₃, —NR⁹R¹⁰, —C(═O)NR⁹R¹⁰, —C(═O)R¹¹, —C(═O)OR¹²,-C₃-C₁₅ cycloalkyl, -(C_(zero)-C₄ alkylene)(C₃-C₂₀cycloalkyl), -(3-15membered) heterocycloalkyl, -C₆-C₁₅ aryl, -(5-15 membered) heteroaryl,—CHO, -(C_(zero)-C₄ alkylene)-(C₃-C₂₀ cycloalkyl), -(C_(zero)-C₄alkylene)-(C₄-C₂₀ cycloalkenyl), (C_(zero)-C₄ alkylene)-((C₁₀-C₂₀)bi- ortricycloalkyl), -(C_(zero)-C₄ alkylene)-((C₁₀-C₂₀)bi- ortricycloalkenyl), -(C_(zero)-C₄ alkylene)-((3-20 membered)heterocycloalkyl), C_(zero)-C₄ alkylene)-(C₆-C₁₅ aryl) and -(C_(zero)-C₄alkylene)-((5-15 membered) heteroaryl), —C(═O)(C₁-C₁₅ alkyl),—C(═O)((5-15 membered)heterocycloalkyl), —C(═O)((5-15 membered)heteroaryl), —C(═O)(C₅-C₁₅ cycloalkyl), —C(═O)O(C₁-C₈ alkyl),—C(═O)N(C₁-C₁₀ alkyl)(C₁-C₁₀ alkyl), C(═O)N(C_(zero)-C₁₀ alkyl)(C₆-C₁₀aryl), —C(═O)N(C_(zero)-C₁₀ alkyl)((5-10 membered) heteroaryl),—C(═O)N(C_(zero)-C₁₀ alkyl)((5-10 membered) heterocycloalkyl),—C(═O)N(C_(zero)-C₁₀ alkyl)(C₅-C₁₀ cycloalkyl), —S(O)_(n)—R¹¹,—S(O)_(n)-(C₁-C₆ alkyl), —S(O)_(n)-(C₃-C₈ cycloalkyl), —S(O)_(n)-alkyl,—S(O)_(n)-cycloalkyl, —S(O)_(n)-(6 to 14 membered) aryl, —S(O)_(n)-(5 to14 membered) heteroaryl, -(C_(zero)-C₄ alkylene)(4-15 membered)heterocycloalkyl, wherein said heterocycloalkyl optionally contains fromone to four double or triple bonds, wherein R⁷ is optionally substitutedwith from one to six fluorine atoms or with from one to threesubstituents independently selected from the group R^(1a);

or alternatively R⁷ is selected from —H, -C₁-C₁₂ alkyl, -C₂-C₁₂ alkenyl,-C₂-C₁₂ alkynyl, -C₁-C₂₀ alkoxy, —F, —Cl, —Br, —I, —CN, —NO₂, -C₃-C₁₅cycloalkyl, -(C_(zero)-C₄ alkylene)(C₃-C₁₅ cycloalkyl), -(3-15 membered)heterocycloalkyl, -C₆-C₁₅ aryl, -(5-15 membered) heteroaryl, —CHO,—C(═O)(C₁-C₁₅ alkyl), —C(═O)((5-15 membered)heterocycloalkyl),—C(═O)((5-15 membered) heteroaryl), —C(═O)(C₅-C₁₅ cycloalkyl),—C(═O)O(C₁-C₈ alkyl), —C(═O)N(C₁-C₁₀ alkyl)(C₁-C₁₀ alkyl),C(═O)N(C_(zero)-C₁₀ alkyl)(C₆-C₁₀ aryl), —C(═O)N(C_(zero)-C₀alkyl)((5-10 membered) heteroaryl), —C(═O)N(C_(zero)-C₁₀ alkyl)((5-10membered) heterocycloalkyl), —C(═O)N(C_(zero)-C₁₀ alkyl)(C₅-C₁₀cycloalkyl), —S(O)_(n)-(C₁-C₆ alkyl), —S(O)_(n)-(C₃-C₈ cycloalkyl),—S(O)_(n)—alkyl, —S(O)_(n)-cycloalkyl, —S(O)_(n)-(6 to 14 membered)aryl, —S(O)_(n)-(5 to 14 membered) heteroaryl, -(C_(zero)-C₄alkylene)(4-15 membered) heterocycloalkyl, wherein said alkyl, alkenyl,alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl areeach optionally independently substituted with from one to threesubstituents independently selected from —F, —Cl, —Br, —I, —OH, -C₁-C₁₀alkyl, -C₂-C₁₀ alkenyl, -C₁-C₁₀ alkoxy, -C₂-C₁₀ alkenoxy, -C₂-C₁₀alkynoxy, —NR⁹R¹⁰, (C₁-C₁i alkyl)—NR⁹R¹⁰, —C(═O)R¹¹, —S(O)_(n)—R¹¹,—C(═O)OR¹², —C(═O)NR⁹R¹⁰, —S(O)_(n)—NR⁹R¹⁰-C₃-C₁₅ cycloalkyl, -(4-15membered) heterocycloalkyl, -C₆-C₁₅ aryl, -(5-15 membered) heteroaryl,(5-15 membered) heterocycloalkoxy, -C₆-C₁₂ aryloxy and (6-12 membered)heteroaryloxy;

or R⁶ and R⁷ may together with the carbon atoms to which they arerespectively attached optionally form a five to fourteen memberedcycloalkyl ring, a five to fourteen membered heterocycloalkyl ring, aten to fourteen membered bicycloalkyl ring or a ten to fourteen memberedbicycloheteroalkyl ring fused to the oxazole ring in the compound ofFormula I, wherein from one to three members of said heterocycloalkylring or said bicycloheteroalkyl ring are selected from N, O and S, andwherein said cycloalkyl, heterocycloalkyl, bicycloalkyl orbicylcoheteroalkyl ring optionally contains from one to three doublebonds; and

R⁸ is selected from —H and -C₁-C₆ alkyl;

or, when Z is —C(═NR⁸)CHR¹R², R⁸ and R¹ may together with the nitrogenand carbon atoms to which they are respectively attached optionally forma five to fourteen membered heteroaryl ring or a five to eight memberedheterocycloalkyl ring, wherein said heteroaryl or heterocycloalkyl ringoptionally contains from one to two further heteroatoms selected from N,O and S, and wherein said heterocycloalkyl ring optionally contains fromone to three double bonds, and wherein said heteroaryl orheterocycloalkyl ring is optionally substituted with from one to threesubstituents independently selected from the group R^(1b);

n is in each instance an integer independently selected from 0, 1, and2;

and the pharmaceutically acceptable salts of such compounds.

Compounds of the Formula I may have optical centers and therefore mayoccur in different enantiomeric, diastereomeric and meso configurations.The present invention includes all enantiomers, diastereomers, and otherstereoisomers of such compounds of the Formula I, as well as racemic andother mixtures thereof. The present invention also includes alltautomers of the Formula I. When the compounds of Formula I of thepresent invention contain one optical center, the “S” enantiomer ispreferred.

Insofar as the compounds of Formula I of this invention contain basicgroups, they can form acid addition salts with various inorganic andorganic acids. The present invention also relates to thepharmaceutically acceptable acid addition salts of compounds of theFormula I. Although such salts must be pharmaceutically acceptable foradministration to animals, it is often desirable in practice toinitially isolate the base compound from the reaction mixture as apharmaceutically unacceptable salt and then simply convert to the freebase compound by treatment with an alkaline reagent, and thereafter,convert the free base to a pharmaceutically acceptable acid additionsalt. The acid addition salts of the base compounds of this inventionare readily prepared by treating the base compound with a substantiallyequivalent amount of the chosen mineral or organic acid in an aqueoussolvent or in a suitable organic solvent, such as methanol or ethanol.Upon careful evaporation of the solvent, the desired solid salt isreadily obtained. The acids which are used to prepare thepharmaceutically acceptable acid addition salts of the aforementionedbase compounds of this invention are those which form non-toxic acidaddition salts, i.e., salts containing pharmaceutically acceptableanions, such as the hydrochloride, hydrobromide, hydroiodide,trifluoroaectic acid, nitrate, sulfate or bisulfate, phosphate or acidphosphate, acetate, lactate, citrate or acid citrate, tartrate orbi-tartrate, succinate, maleate, fumarate, gluconate, saccharate,benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate))salts. Other examples ofpharmaceutically acceptable salts of the compounds of this invention arethe salts of salicylic acid, oxalic acid, di-p-toluoyl tartaric acid,mandelic acid, sodium, potassium, magnesium, calcium and lithium.

The present invention also includes isotopically-labeled compounds thatare identical to those recited in Formula I, but for the fact that oneor more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. Examples of isotopes that can be incorporated into the compoundsof the present invention include isotopes of hydrogen, carbon, nitrogen,oxygen, phosphorous, fluorine, chlorine and iodine, such as ²H, ³H, ¹³C,¹¹C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ¹⁸F, ¹²³I and ¹²⁵I, respectively. The compoundsof Formula I of the present invention, prodrugs thereof,pharmaceutically acceptable salts of such compounds or of such prodrugs,and compounds and derivatives of such compounds that contain theaforementioned isotopes and/or other isotopes are within the scope ofthis invention. Such compounds may be useful as research and diagnostictools in metabolism pharmacokinetic studies and in binding assays.Certain isotopically-labeled compounds of the Formula I of the presentinvention, for example, those into which radioactive isotopes such as ³Hand ¹⁴C are incorporated, are useful in drug and/or substrate tissuedistribution assays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C,isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium, i.e., ²H, can afford certain therapeutic advantages resultingfrom greater metabolic stability, for example increased in vivohalf-life or reduced dosage requirements and, hence, may be preferred insome circumstances. Isotopically-labeled compounds of the Formula I ofthe present invention and prodrugs and derivatives thereof may generallybe prepared by carrying out the procedures disclosed in the schemes anddiscussion of the schemes and/or in the examples and preparationsdescribed herein, by substituting a readily availableisotopically-labeled reagent for a nonisotopically-labeled reagent inthe preparation of said compounds.

Unless otherwise indicated, as used herein, the terms “halogen” and“halo” include F, Cl, Br and I.

Unless otherwise indicated, as used herein, the term “alkyl” includessaturated monovalent hydrocarbon radicals having straight or branchedmoieties. Examples of alkyl groups include, but are not limited to,methyl, ethyl, n-propyl, isopropyl, cyclopropylmethylene(—CH₂-cyclopropyl) and t-butyl.

Unless otherwise indicated, as used herein, the term “alkenyl” includesalkyl moieties having at least one carbon-carbon double bond whereinalkyl is as defined above. Examples of alkenyl include, but are notlimited to, ethenyl and propenyl.

Unless otherwise indicated, as used herein, the term “alkynyl” includesalkyl moieties having at least one carbon-carbon triple bond whereinalkyl is as defined above. Examples of alkynyl groups include, but arenot limited to, ethynyl and 2-propynyl.

Unless otherwise indicated, as used herein, the term “alkoxy”, means“alkyl-O—”, wherein “alkyl” is as defined above. Examples of “alkoxy”groups include, but are not limited to, methoxy, ethoxy, propoxy,butoxy, pentoxy and allyloxy.

Unless otherwise indicated, as used herein, the term “alkenoxy”, means“alkenyl-O-”, wherein “alkenyl” is as defined above.

Unless otherwise indicated, as used herein, the term “alkynoxy”, means“alkynyl-O-”, wherein “alkynyl” is as defined above.

In all of the above defined “C₁-C_(x) alkyl,” “C₁-C_(x) alkenyl,”“C₁-C_(x) alkynyl,” “C₁-C_(x) alkoxy,” “C₁-C_(x) alkenoxy,” and“C₁-C_(x) alkynoxy,” groups, when x is an integer greater than 2, such“C₁-C_(x) alkyl,” “C₁-C_(x) alkenyl,” “C₁-C_(x) alkynyl,” “C₁-C_(x)alkoxy,” “C₁-C_(x) alkenoxy,” and “C₁-C_(x) alkynoxy,” groups, mayoptionally be replaced with a “polyfluoro C₁-C_(x) alkyl,” a polyfluoroC₁-C_(x) alkenyl,” a “polyfluoro C₁-C_(x) alkynyl,” a “polyfluoroC₁-C_(x) alkoxy,” a “polyfluoro C₁-C_(x) alkenoxy,” or a “polyfluoroC₁-C_(x) alkynoxy,” group. As used herein, the expression “polyfluoroC₁-C_(x) alkyl” refers to alkyl groups, as defined above, that compriseat least one —CF₂ and/or CF₃ group.

Unless otherwise indicated, as used herein, the term “cycloalkyl”includes non-aromatic saturated cyclic alkyl moieties wherein alkyl isas defined above. Examples of cycloalkyl groups include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, andcycloheptyl. “Bicycloalkyl” and “tricycloalkyl” groups are non-aromaticsaturated cyclic alkyl moieties consisting of two or three rings,respectively, wherein said rings share at least one carbon atom. Forpurposes of the present invention, and unless otherwise indicated,bicycloalkyl groups include spiro groups and fused ring groups. Examplesof bicycloalkyl groups include, but are not limited to,bicyclo-[3.1.0]-hexyl, bicyclo-[2.2.1]-hept-1-yl, norbornyl,spiro[4.5]decyl, spiro[4.4]nonyl, spiro[4.3]octyl, and spiro[4.2]heptyl.An example of a tricycloalkyl group is adamantanyl. Other cycloalkyl,bicycloalkyl, and tricycloalkyl groups are known in the art, and suchgroups are encompassed by the definitions “cycloalkyl”, “bicycloalkyl”and “tricycloalkyl” herein. “Cycloalkenyl”, “bicycloalkenyl” and“tricycloalkenyl” refer, respectively, to non-aromatic cycloalkyl,bicycloalkyl and tricycloalkyl moieties, respectively, as defined above,except that they each include one or more carbon-carbon double bondsconnecting carbon ring members (an “endocyclic” double bond) and/or oneor more carbon-carbon double bonds connecting a carbon ring member andan adjacent non-ring carbon (an “exocyclic” double bond). Examples ofcycloalkenyl groups include, but are not limited to, cyclopentenyl,cyclobutenyl, and cyclohexenyl. A non-limiting example of abicycloalkenyl group is norbornenyl. Cycloalkyl, cycloalkenyl,bicycloalkyl, and bicycloalkenyl groups also include groups that aresubstituted with one or more oxo moieties. Examples of such groups withoxo moieties are oxocyclopentyl, oxocyclobutyl, oxocyclopentenyl andnorcamphoryl. Other cycloalkenyl, bicycloalkenyl, and tricycloalkenylgroups are known in the art, and such groups are included within thedefinitions “cycloalkenyl”, “bicycloalkenyl” and “tricycloalkenyl”herein.

Unless otherwise indicated, as used herein, the term “aryl” includes anorganic radical derived from an aromatic hydrocarbon by removal of onehydrogen, such as phenyl (Ph), naphthyl, indenyl, indanyl and fluorenyl.“Aryl” encompasses fused ring groups wherein at least one ring isaromatic.

Unless otherwise indicated, as used herein, the terms “heterocyclic” and“heterocycloalkyl” refer to non-aromatic cyclic groups containing one ormore heteroatoms, preferably from one to four heteroatoms, eachindependently selected from O, S and N. “Heterobicycloalkyl” groups arenon-aromatic two-ringed cyclic groups, wherein said rings share one ortwo atoms, and wherein at least one of the rings contains a heteroatom(O, S, or N). Unless otherwise indicated, for purposes of the presentinvention, heterobicycloalkyl groups include spiro groups and fused ringgroups. In one embodiment, each ring in the heterobicycloalkyl groupcontains up to four heteroatoms (i.e. from zero to four heteroatoms,provided that at least one ring contains at least one heteroatom). Theheterocyclic groups of this invention can also include ring systemssubstituted with one or more oxo moieties. Examples of non-aromaticheterocyclic groups are aziridinyl, azetidinyl, pyrrolidinyl,piperidinyl, azepinyl, piperazinyl, 1,2,3,6-tetrahydropyridinyl,oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl,tetrahydropyranyl, tetrahydrothiopyranyl, morpholino, thiomorpholino,thioxanyl, pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,1,3-dioxolanyl, pyrazolinyl, dihydropyranyl, dihydrothienyl,dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, quinolizinyl,quinuclidinyl, 1,4-dioxaspiro[4.5]decyl, 1,4-dioxaspiro[4.4]nonyl,1,4-dioxaspiro[4.3]octyl, and 1,4-dioxaspiro[4.2]heptyl.

Unless otherwise indicated, as used herein, “heteroaryl” refers toaromatic groups containing one or more heteroatoms, preferably from oneto four heteroatoms, selected from O, S and N. A multicyclic groupcontaining one or more heteroatoms wherein at least one ring of thegroup is aromatic is a “heteroaryl” group. The heteroaryl groups of thisinvention can also include ring systems substituted with one or more oxomoieties. Examples of heteroaryl groups are pyridinyl, pyridazinyl,imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl,isoquinolyl, 1,2,3,4-tetrahydroguinolyl, tetrazolyl, furyl, thienyl,isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl,benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl,phthalazinyl, triazinyl, 1,2,4-trizainyl, 1,3,5-triazinyl, isoindolyl,1-oxoisoindolyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl,benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl,benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl,dihydroquinolyl, tetrahydroquinolyl, dihydroisoquinolyl,tetrahydroisoquinolyl, benzofuryl, furopyridinyl, pyrolopyrimidinyl, andazaindolyl.

Unless otherwise indicated, as used herein, the term “cycloalkoxy”,means “cycloalkyl-O—”, wherein “cycloalkyl” is as defined above.

Unless otherwise indicated, as used herein, the term “aryloxy”, means“aryl-O—”, wherein “aryl” is as defined above.

Unless otherwise indicated, as used herein, the term“heterocycloalkoxy”, means “heterocycloalkyl-O—”, wherein“heterocycloalkyl” is as defined above.

Unless otherwise indicated, as used herein, the term “heteroaryloxy”,means “heteroaryl-O—”, wherein “heteroaryl” is as defined above.

The foregoing groups, as derived from the compounds listed above, may beC-attached or N-attached where such is possible. For instance, a groupderived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl(C-attached). The terms referring to the groups also encompass allpossible tautomers.

In one aspect, the present invention relates to compounds of the FormulaI, wherein the stereochemistry of the R³ substituent is as shown informula I-A below.

In another aspect, the present invention relates to compounds ofFormulas I and IA, wherein Z is —C(═O)CHR¹R, R¹ is —H, —OH, orOC(═O)CH₃.

In another aspect, the present invention relates to compounds of theFormulas I and IA, wherein Z is —C(═O)C(═O)R¹.

In another aspect, the present invention relates to compounds of theFormulas I and IA, wherein Z is —SO₂R¹.

In another aspect, the present invention relates to compounds of theFormula I wherein R¹ is selected from -C₁-C₂₀ alkyl, -C₂-C₂₀ alkenyl,-C₂-C₂₀ alkynyl, -C₃-C₂₀ cycloalkyl, (4-20 membered) heterocycloalkyl,-C₆-C₂₀ aryl and (5-20 membered) heteroaryl.

In another aspect, R¹ is selected from -C₁-C₁₀ alkyl, -C₂-C₁₀ alkenyl,-C₃-C₁₀ cycloalkyl, phenyl, thienyl, and pyridyl, wherein R¹ isoptionally independently substituted with from one to two substituentsindependently selected from -C₁-C₄ alkyl, —CF₃, -C₁-C₄ alkoxy, —F, —Cl,—Br, phenyl and phenoxy, wherein R¹ optionally contains one or twodouble or triple bonds.

In another aspect, R¹ is -C₃-C₇ cycloalkyl, e.g., [2.2.1]-heptanyl.

In another aspect, R¹ is selected from phenyl and pyridyl, wherein R¹ isoptionally independently substituted with from one to two substituentsindependently selected from —F, —Cl and —CF₃.

In another aspect, the present invention relates to compounds of theFormula I wherein R² is selected from —H, —OH, —NH₂ and —OC(═O)CH₃.

In another aspect, R² is selected from —H and —OH.

In another aspect, R² is selected from —OC(═O)CH₃.

In another aspect, the present invention relates to compounds of theFormula I wherein R³ is selected from -C₁-C₄ alkyl, allyl, and—CH₂CH₂SCH₃.

In another aspect, the present invention relates to compounds of theFormula I wherein R⁵ is H.

In another aspect, the present invention relates to compounds of theFormula I wherein R⁶ is selected from —H, CH₃, —F, —Cl, —Br —CF₃, and—C(═O)R¹¹.

In another aspect, R⁶ is —H.

In another aspect, R⁶is —CH₃.

In another aspect, R¹ is —F.

In another aspect, R⁶is —CF₃.

In another aspect, R⁷ is selected from —H, -C₁-C₂₀ alkyl, -C₂-C₂₀alkenyl, -C₂-C₂₀ alkynyl, -C₁-C₂₀ alkoxy, -C₂-C₂₀ alkenoxy, -C₂-C₂₀alkynoxy, —F, —Cl, —Br, —I, —CN, —NO₂, —OH, —CF₃, —NR⁹R¹⁰, —C(═O)NR⁹R¹⁰,—C(═O)R¹¹, —CHO, —S(O)_(n)—R¹¹, —C(═O)OR¹², -(C_(zero)-C₄alkylene)-(C₃-C₂₀ cycloalkyl), C_(zero)-C₄ alkylene)-(C₄-C₂₀cycloalkenyl), -(C_(zero)-C₄ alkylene)-((C₁₀-C₂₀)bi- or tricycloalkyl),C_(zero)-C₄ alkylene)-((C₁₀-C₂₀)bi- or tricycloalkenyl), -(C_(zero)-C₄alkylene)-((3-20 membered) heterocycloalkyl), -(C_(zero)-C₄alkylene)-(C₆-C₁₅ aryl) and C_(zero)-C₄ alkylene)-((5-15 membered)heteroaryl), wherein said heterocycloalkyl optionally contains from oneto four double or triple bonds wherein R⁷ is optionally substituted withfrom one to six fluorine atoms or with from one to three substituentsindependently selected from the group R^(1a).

Specific embodiments of the present invention include the followingcompounds of Formula I, all pharmaceutically acceptable salts thereof,complexes thereof, and derivatives thereof that convert into apharmaceutically active compound upon administration:

-   2-{2-[2-(3,5-Difluoro-phenyl)-acetylamino]-butyrylamino}-4-trifluoromethyl-oxazole-5-carboxylic    acid ethyl ester;-   2-[2-(3-Phenoxy-phenyl)-acetylamino]-pentanoic acid    (5-benzoyl-oxazol-2-yl)-amide;-   2-[2-(3-Phenoxy-phenyl)-acetylamino]-pentanoic acid    (5-acetyl-oxazol-2-yl)-amide;-   2-[2-(3-Phenoxy-phenyl)-acetylamino]-pentanoic acid    (5-phenyl-oxazol-2-yl)-amide;-   2-[2-(3-Phenoxy-phenyl)-acetylamino]-pentanoic acid    (4,5-dimethyl-oxazol-2-yl)-amide;-   2-[2-(3-Phenoxy-phenyl)-acetylamino]-pentanoic acid    [5-(thiophene-2-carbonyl)-oxazol-2-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    [5-(hydroxy-phenyl-methyl)-4-methyl-oxazol-2-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    (5-acetyl-oxazol-2-yl)-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    [5-(4-fluoro-benzoyl)-oxazol-2-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    [5-(3-bromo-benzoyl)-oxazol-2-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    {5-[1-(3-methyl-butylamino)-ethyl]-oxazol-2-yl}-amide;-   2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid    (5-acetyl-oxazol-2-yl)-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    (5-acetyl-oxazol-2-yl)-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    [5-(1-hydroxy-ethyl)-oxazol-2-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    {5-[1-(3,3-dimethyl-butylamino)-ethyl]-oxazol-2-yl}-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    {5-[1-(2,2,2-trifluoro-ethylamino)-ethyl]-oxazol-2-yl}-amide;-   2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid    {5-[1-(3,3-dimethyl-butylamino)-ethyl]-oxazol-2-yl}-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    {5-[1-(3-methyl-butylamino)-ethyl]-oxazol-2-yl}-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    [5-(1-isobutylamino-ethyl)-oxazol-2-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    (5-hydroxymethyl-4-trifluoromethyl-oxazol-2-yl)-amide;-   2-(2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoylamino)-4-trifluoromethyl-oxazole-5-carboxylic    acid methyl ester;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    {5-[1-(3-methyl-butylamino)-ethyl]-oxazol-2-yl}-amide hydrogen    chloride;-   2-[2-(5-Phenoxy-3-pyridyl)-acetylamino]-pentanoic acid    (5-benzoyl-oxazol-2-yl)-amide;-   2-[2-(5-Phenoxy-3-pyridyl)-acetylamino]-pentanoic acid    (5-acetyl-oxazol-2-yl)-amide;-   2-[2-(5-Phenoxy-3-pyridyl)-acetylamino]-pentanoic acid    (5-phenyl-oxazol-2-yl)-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-propanoic acid    [4-(phenyl)-5-(ethyl)-oxazol-2-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-carboxylic    acid ethyl ester -oxazol-2-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    [5-(2-hyroxypropyl)-oxazol-2-yl]-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    {5-(carboxy)-oxazol-2-yl}-amide;-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    {5-(phenyl)-oxazol-2-yl}-amide; and-   2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid    [(5-carboxylic acid ethyl    ester-5-trifluoromethyl)oxazol-2-yl]-amide.

Compounds of the Formula I of this invention, and their pharmaceuticallyacceptable salts, have useful pharmaceutical and medicinal properties.The compounds of Formula I, and their pharmaceutically acceptable saltsinhibit the production of Aβ-peptide (thus, gamma-secretase activity) inmammals, including humans. Compounds of the Formula I, and theirpharmaceutically acceptable salts, are therefore able to function astherapeutic agents in the treatment of the neurodegenerative and/orneurological disorders and diseases enumerated below, for exampleAlzheimer's disease, in an afflicted mammal, including a human.

The present invention also relates to a pharmaceutical composition forinhibiting or modulating Aβ-peptide production in a mammal, including ahuman, comprising an amount of a compound of the Formula I, or apharmaceutically acceptable salt thereof, that is effective ininhibiting Aβ-production, and a pharmaceutically acceptable carrier.

The present invention also relates to a pharmaceutical composition fortreating a disease or condition selected from the group consisting ofAlzheimer's disease, hereditary cerebral hemorrhage with amyloidosis,cerebral amyloid angiopathy, a prion-mediated disease, inclusion bodymyositis, stroke, multiple sclerosis and Down's Syndrome in a mammal,including a human, comprising an amount of a compound of the Formula I,or a pharmaceutically acceptable salt thereof, that is effective ininhibiting Aβ-peptide production, and a pharmaceutically acceptablecarrier.

The present invention also relates to a pharmaceutical composition fortreating a disease or condition selected from the group consisting ofAlzheimer's disease and Down's Syndrome in a mammal, including a human,comprising an amount of a compound of the Formula I, or apharmaceutically acceptable salt thereof, that is effective ininhibiting Aβ-peptide production, and a pharmaceutically acceptablecarrier.

The present invention also relates to a pharmaceutical composition fortreating a disease or a condition selected from the group consisting ofAlzheimer's disease, hereditary cerebral hemorrhage with amyloidosis,cerebral amyloid angiopathy, a prion-mediated disease, inclusion bodymyositis, stroke, multiple sclerosis and Down's Syndrome in a mammal,including a human, comprising an amount of a compound of the Formula I,or a pharmaceutically acceptable salt thereof, that is effective intreating such disease or condition, and a pharmaceutically acceptablecarrier.

The present invention also relates to a pharmaceutical composition fortreating a disease or a condition selected from the group consisting ofAlzheimer's disease and Down's Syndrome in a mammal, including a human,comprising an amount of a compound of the Formula I, or apharmaceutically acceptable salt thereof, that is effective in treatingsuch disease or condition, and a pharmaceutically acceptable carrier.

The present invention also relates to a method of inhibiting Aβ-peptideproduction in a mammal, including a human, comprising administering tosaid mammal an amount of a compound of the Formula I, or apharmaceutically acceptable salt thereof, that is effective ininhibiting Aβ-production.

The present invention also relates to a method of treating a disease orcondition selected from Alzheimer's disease, hereditary cerebralhemorrhage with amyloidosis, cerebral amyloid angiopathy, aprion-mediated disease, inclusion body myositis, stroke, multiplesclerosis and Down's Syndrome in a mammal, including a human, comprisingadministering to said mammal an amount of a compound of the Formula I,or a pharmaceutically acceptable salt thereof, that is effective ininhibiting Aβ-production.

The present invention also relates to a method of treating a disease orcondition selected from Alzheimer's disease and Down's Syndrome in amammal, including a human, comprising administering to said mammal anamount of a compound of the Formula I, or a pharmaceutically acceptablesalt thereof, that is effective in inhibiting Aβ-production.

The present invention also relates to a method of treating a disease orcondition selected from Alzheimer's disease, hereditary cerebralhemorrhage with amyloidosis, cerebral amyloid angiopathy, aprion-mediated disease, inclusion body myositis, stroke, multiplesclerosis and Down's Syndrome in a mammal, including a human, comprisingadministering to said mammal an amount of a compound of the Formula I,or a pharmaceutically acceptable salt thereof, that is effective intreating such condition.

The present invention also relates to a method of treating a disease orcondition selected from Alzheimer's disease and Down's Syndrome in amammal, including a human, comprising administering to said mammal anamount of a compound of the Formula I, or a pharmaceutically acceptablesalt thereof, that is effective in treating such condition.

The present invention also relates to a pharmaceutical composition fortreating a disease or condition associated with Aβ-peptide production ina mammal, including a human, comprising (a) a compound of the Formula I,or a pharmaceutically acceptable salt thereof; (b) a memory enhancementagent, antidepressant, anxiolytic, antipsychotic agent, sleep disorderagent, anti-inflammatory agent, anti-oxidant agent, cholesterolmodulating agent or anti-hypertensive agent; and (c) a pharmaceuticallyacceptable carrier; wherein the active agents “a” and “b” above arepresent in amounts that render the composition effective in treatingsuch disease or condition.

The present invention also relates to a pharmaceutical composition fortreating a disease or condition selected from the group consisting ofAlzheimer's disease, hereditary cerebral hemorrhage with amyloidosis,cerebral amyloid angiopathy, a prion- mediated disease, inclusion bodymyositis, stroke, multiple sclerosis and Down's Syndrome, in a mammal,including a human, comprising (a) a compound of the Formula I, or apharmaceutically acceptable salt thereof; (b) a memory enhancementagent, antidepressant, anxiolytic, antipsychotic agent, sleep disorderagent, anti-inflammatory agent, anti-oxidant agent, cholesterolmodulating agent or anti-hypertensive agent; and (c) a pharmaceuticallyacceptable carrier; wherein the active agents “a” and “b” above arepresent in amounts that render the composition effective in treatingsuch disease or condition.

The present invention also relates to a pharmaceutical composition fortreating a disease or condition selected from the group consisting ofAlzheimer's disease and Down's Syndrome, in a mammal, including a human,comprising (a) a compound of the Formula I, or a pharmaceuticallyacceptable salt thereof; (b) a memory enhancement agent, antidepressant,anxiolytic, antipsychotic agent, sleep disorder agent, anti-inflammatoryagent, anti-oxidant agent, cholesterol modulating agent oranti-hypertensive agent; and (c) a pharmaceutically acceptable carrier;wherein the active agents “a” and “b” above are present in amounts thatrender the composition effective in treating such disease or condition.

The present invention also relates to a method of treating a disease orcondition associated with Aβ-peptide production in a mammal, including ahuman, comprising administering to said mammal (a) a compound of theFormula I, or a pharmaceutically acceptable salt thereof; and (b) amemory enhancement agent, antidepressant, anxiolytic, antipsychoticagent, sleep disorder agent, anti-inflammatory agent, anti-oxidantagent, cholesterol modulating agent or anti-hypertensive agent; whereinthe active agents “a” and “b” above are present in amounts that renderthe composition effective in treating such disease or condition.

The present invention also relates to a method of treating a disease orcondition selected from the group consisting of Alzheimer's disease,hereditary cerebral hemorrhage with amyloidosis, cerebral amyloidangiopathy, a prion-mediated disease, inclusion body myositis, stroke,multiple sclerosis and Down's Syndrome, in a mammal, including a human,comprising administering to said mammal (a) a compound of the Formula I,or a pharmaceutically acceptable salt thereof; and (b) a memoryenhancement agent, antidepressant, anxiolytic, antipsychotic agent,sleep disorder agent, anti-inflammatory agent, anti-oxidant agent,cholesterol modulating agent or anti-hypertensive agent; wherein theactive agents “a” and “b” above are present in amounts that render thecomposition effective in treating such disease or condition.

The present invention also relates to a method of treating a disease orcondition selected from the group consisting of Alzheimer's disease andDown's Syndrome, in a mammal, including a human, comprisingadministering to said mammal (a) a compound of the Formula I, or apharmaceutically acceptable salt thereof; and (b) a memory enhancementagent, antidepressant, anxiolytic, antipsychotic agent, sleep disorderagent, anti-inflammatory agent, anti-oxidant agent, cholesterolmodulating agent or anti-hypertensive agent; wherein the active agents“a” and “b” above are present in amounts that render the compositioneffective in treating such disease or condition.

Compounds of the Formula I may be used alone or used as a combinationwith any other drug, including, but not limited to, any memoryenhancement agent, e.g., Aricept™, antidepressant agent, e.g., Zoloft™,anxiolytic, antipsychotic agent, e.g., Geodon™, sleep disorder agent,anti-inflammatory agent, e.g., Celebrex™, Bextra™, etc., anti-oxidantagent, cholesterol modulating agent (for example, an agent that lowersLDL or increases HDL), e.g., Lipitor™, or anti-hypertension agent.Accordingly, this invention also provides a pharmaceutical compositionfor treatment of a mammal, including a human, in need thereof comprisingan effective amount of a compound of the Formula I and an effectiveamount of another drug, for example a memory enhancement agent, e.g.,Aricept™, antidepressant agent, e.g., Zoloft™, anxiolytic, antipsychoticagent, e.g., Geodon™, sleep disorder agent, anti-inflammatory agent,e.g., Celebrex™, Bextra™, etc., anti-oxidant agent, cholesterolmodulating agent (for example, an agent that lowers LDL or increasesHDL), e.g., Lipitor™, or anti-hypertension agent, and a pharmaceuticallyacceptable carrier. This invention also provides a method for treatingdementia, for example Alzheimer's disease, in a mammal, including in ahuman, comprising administering to the mammal an effective amount of acompound of the Formula I and an effective amount of another drug, forexample a memory enhancement agent, e.g., Aricept™, antidepressantagent, e.g., Zoloft™, anxiolytic, antipsychotic agent, e.g., Geodon™,sleep disorder agent, anti-inflammatory agent, e.g., Celebrex™, Bextra™,etc., anti-oxidant agent, cholesterol modulating agent (for example, anagent that lowers LDL or increases HDL), e.g., Lipitor™, oranti-hypertension agent.

Compounds of the Formula I, or any of the combinations described in theimmediately preceding paragraph, may optionally be used in conjunctionwith a know P-glycoprotein inhibitor, such as verapamil.

References herein to diseases and conditions “associated with Aβ-peptideproduction” relate to diseases or conditions that are caused, at leastin part, by Aβ-peptide and/or the production thereof. Thus, Aβ-peptideis a contributing factor, but not necessarily the only contributingfactor, to “a disease or condition associated with Aβ-peptideproduction.”

As used herein, the term “treating” refers to reversing, alleviating orinhibiting the progress of a disease, disorder or condition, or one ormore symptoms of such disease, disorder or condition, to which such termapplies. As used herein, “treating” may also refer to decreasing theprobability or incidence of the occurrence of a disease, disorder orcondition in a mammal as compared to an untreated control population, oras compared to the same mammal prior to treatment. For example, as usedherein, “treating” may refer to preventing a disease, disorder orcondition, and may include delaying or preventing the onset of adisease, disorder or condition, or delaying or preventing the symptomsassociated with a disease, disorder or condition. As used herein,“treating” may also refer to reducing the severity of a disease,disorder or condition or symptoms associated with such disease, disorderor condition prior to a mammal's affliction with the disease, disorderor condition. Such prevention or reduction of the severity of a disease,disorder or condition prior to affliction relates to the administrationof the composition of the present invention, as described herein, to asubject that is not at the time of administration afflicted with thedisease, disorder or condition. As used herein “treating” may also referto preventing the recurrence of a disease, disorder or condition or ofone or more symptoms associated with such disease, disorder orcondition. The terms “treatment” and “therapeutically,” as used herein,refer to the act of treating, as “treating” is defined above.

DETAILED DESCRIPTION OF THE INVENTION

Compounds of the Formula I, and their pharmaceutically acceptable salts,may be prepared as described in the following reaction Schemes anddiscussion. Unless otherwise indicated, as referred to in the reactionschemes and discussion that follow, R¹, R^(1a), R^(1b), R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹² and Z are as defined above.

The compounds of Formula I may have asymmetric carbon atoms and maytherefore exist as racemic mixtures, diastereoisomers, geometricisomers, or as individual optical isomers.

Separation of a mixture of isomers of compounds of Formula I into singleisomers may be accomplished according to conventional methods known inthe art.

The compounds of the Formula I may be prepared by the methods describedbelow, together with synthetic methods known in the art of organicchemistry, or modifications and derivatizations that are familiar tothose of ordinary skill in the art. Preferred methods include, but arenot limited to, those described below.

The reactions described below are performed in solvents that areappropriate to the reagents and materials employed and that are suitablefor use in the reactions described. In the description of the syntheticmethods described below, it is also to be understood that all reactionconditions, whether actual or proposed, including choice of solvent,reaction temperature, reaction duration time, reaction pressure, andother reaction conditions (such as anhydrous conditions, under argon,under nitrogen, etc.), and work up procedures, are those conditions thatare standard for that reaction, as would be readily recognized by one ofskill in the art. Alternate methods may also be used.

Scheme I refers to a method of preparation of compounds of the FormulaI, 10. An aminooxazole 1 is coupled with a nitrogen-protected amino acid2a-c using conventional coupling reagents and procedures. The nitrogenprotecting group may be a carbamate-type such as butoxycarbonyl (“BOC”,Y=tert-butyl) or benzyloxycarbonyl (“CBZ”, Y=benzyl) that is preparedwith either di-tert-butyl dicarbonate (Aldrich Chemical Company,Milwaukee, Wis.), or benzyl chloroformate (Aldrich) in the presence ofeither an inorganic or organic base (e.g., sodium carbonate ortriethylamine) at 0 to 30° C. in an organic solvent (e.g., methylenechloride) or in a mixture of water and an organic solvent (e.g., ethylacetate) (Scheme II) (see, Muller, Methoden Der Oraanischen Chemie.“Vierte Auglage-Synthesis von Peptiden I”-Houben Weyl-Georg-ThiemeVerlag Stuttgart, 1974, Band XV/1).

The amino-oxazoles 1 starting reagents may be prepared according to theprocedure known in literature (references: Bioorg. Med. Chem. Lett.; 12;10; 2002; 1379-1382; Yakugaku Zasshi; 91; 1971, 425, 429, 430, 485, 487;Chem. Abstr. 75; 35848, 48692, 1971; Chem. Abstr., 79; 146503;Tetrahedron Lett., 25; 28; 1984; 2957-2960; Justus Liebigs Ann. Chem.;596; 1955; 1, 117; J. Chem. Soc., 1934, 1186, 1190; Chem. Ber., 99,1966, 2110, 2117; Zh. Obshch. Khim., 29; 1959, 2330, 2336; engl. Ausg.S. 2294, 2299; J. Org. Chem. USSR (Engl. Transl.), 19, 1983, 818-820; J.Amer. Chem. Soc., 75; 1953, 2770; J. Chem. Soc. Perkin Trans. 1, 1978;249-252; Arch. Pharm. (Weinheim Ger.), 286, 1953, 494, 499; J. Org.Chem., 49, 3 1984, 566-570.) For example, compounds of formula I can beobtained by reacting a compound of formula VII, wherein L¹ is a leavinggroup such as a bromine, chlorine or iodine, with urea in a suitablesolvent or a mixture of solvents, such as C₁-C₄ alcohol, THF,1,4-dioxane, toluene, water, methylene chloride, or chloroform, at asuitable temperature, such as from about 0° C. to about reflux.

Numerous reagents that are well-known in the art may be used to couple 1and 2a-c to form 3 by standard peptide coupling methods (La) or thetrimethylaluminum coupling method (2b) or a leaving group (halogen or amixed anhydride)(2c) known in art of organic chemistry (Scheme I).Activation of the carboxylic acid 2a with oxalyl halide, thionylchloride, carbodiimidazole, or chloro-(C₁-C₄)alkyl-formate, in thepresence of an appropriate base (e.g., trialkylamine, pyridine,dimethylaminopyridine or sodium carbonate, or the like) or carbodiimideswith or without the use of known additives such as N-hydroxysuccinimide,1-hydroxybenzotriazole, etc. can be used to facilitate coupling.Standard coupling agents include HATU(O-(7-azabenzotriazole-1yl)-1,1,3,3,-tetramethyluroniumhexafluorophosphate) or PyBOP(benzotriazole-1-yl)-oxy-tris-pyrrolidino-phosphoniumhexafluorophosphate) or HBTU(O-benzotriazole-1yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate)/trialkylamine, or 1-hydroxybenzotriazole(HOBT)/1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride(EDAC)/trialkylamine (NEt3), in an appropriate solvent such as methylenechloride, chloroform, tetrahydrofuran (THF), acetonitrile,dimethylformamide (DMF), and the like or a mixture of two solvents tohave reagents mixed well to form a clear solution. Peptide couplingagents or resins for solid phase synthesis such as Fmoc(Fluorenylmethylcarbonyl)-protected hydroxylamine bound to polystylenebeads are common and well known in the literature. Deprotection of theFmoc group under standard conditions using 20% piperidine in DMF.References :O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (“HBTU”, Aldrich Chemical Company) andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (“HATU”, Aldrich) (See, Fieser, Reagents for OrganicSynthesis, 1986, Wiley Interscience, New York, Vol. 12, p. 44; Hruby,Biorganic Chemistry: Peptides and Proteins, 1998, Oxford Universitypress, New York, pp. 27-64; Muller, Methoden Der Organischen Chemie,Vierte Auflage—Synthese von Peptiden II—Houben Weyl, George-ThiemeVerlag Stuttgart, 1974, Band XV/2). When optically active reagents areemployed, reaction conditions, such as temperature, time and theselection of the base, must be carefully controlled to avoidracemization. The protected amino group or carboxylic acid group may beprepared by methods well known in the literature for amino acidprotecting groups as described in Organic chemistry Journal, textbooksuch as “Protective Groups in Organic Synthesis” by T. W. Green.Alternatively, the coupling can be performed by reacting 1 with theester 2b in the presence of trialkylaluminum in an appropriate solvent,e.g., THF, dioxane, toluene or a mixture of THF/toluene in an open orsealed tube at a temperature between 0° C.-120° C. until the completeconversion to the desired product (3 in Scheme I); preferred temperatureis room temperature to 80° C.

Intermediate 3 of Scheme I, is deprotected to afford aminoamide 4 eitherthrough treatment with strong acid in the case of t-butoxycarbonyl orthrough hydrogenolysis in the case of carbobenzyloxycarbonyl.Specifically, t-BOC-3, on treatment with hydrochloric acid ortrifluoroacetic acid in an organic solvent (e.g., dioxane, THF, ormethylene chloride), at room temperature to 30° C. for about 1 hour toabout 19 hours, affords the corresponding salts 4. Alternatively, CBZ-3may be deprotected through catalytic hydrogenolysis in the presence ofhydrogen (from about 1 to about 10 atmospheres), a heavy metal catalyst(e.g., palladium on carbon or palladium hydroxide on carbon, 1 to 10percent catalyst loading, present at about 0.01 to about 0.50 times theof substrate), and a solvent (e.g., methanol, ethanol or ethyl acetate)at 20 to 50° C. for about 1 hour to about 19 hours.

The compound Formula I 10 in Scheme I may be prepared by the reaction of4 with 9 where L is a leaving group (e.g., halide, mesylate, ortriflate) and Z is as defined above. The reaction is carried out at 0 to30° C. in an organic solvent (e.g., methylene chloride, ethyl acetate,or DMF) in the presence of an organic base (e.g., triethylamine,diisopropylethylamine, or N-methylmorpholine) for about 1 minute toabout 24 hours.

Alternatively, the compound Formula I 10 may be prepared according tothe procedure of Scheme II (Z-L is a carboxylic acid or L is a leavinggroup), employing the general conditions described for Scheme I. InScheme II, R can be alkyl or benzyl. The coupling of 9 and 11 in SchemeII may be performed at a temperature of about 0 to 30° C. in an organicsolvent (e.g., methylene chloride, dichloroethane, ethyl acetate, orDMF) in the presence of a base (e.g., triethylamine ordiisopropylethylamine). When R is alkyl, either acidic or basichydrolysis may be used to covert 12 to 13. If R is benzyl, catalytichydrogenolysis may also be used to prepare 13.

The above amide bond formation may be achieved by coupling the ester (12in Scheme II) with 2 in the presence of trialkylaluminum (e.g., AlMe3)in an appropriate solvent, e.g., THF, toluene or a mixture ofTHF/toluene, or similar like solvents in an open or sealed tube at atemperature of about 0° C.-110° C. until there is complete conversion tothe desired product (10 in Scheme II). Preferably, the temperature isabout room temperature to about 80° C.

The ester group of R⁷ may be converted to the corresponding amide usinga similar method for amide bond formation, preferably employingtrimethylaluminum in an appropriate solvent or a mixture of solvents,such as THF/toluene to the corresponding amide.

The keto group of R⁷ may be converted to the corresponding amine using awell-established reductive amination method by reacting a ketone with anappropriate amine with or without acid catalyst or Lewis acid catalyst(Ti(iPrO)₄, ZnCl₂, NiCl₂, /sodium acetate/dry agents (such as activatedmolecular sieves 4A, anhydrous Na₂SO₄ or MgSO₄), and a reducing agentsuch as sodium triacetoxy borohydride, sodium cyanoborohydride, sodiumborohydride, Zn(BH₄)₂, Bu3SnH, Bu2SnCIH, Bu2SnIH, decaborane, silicagel-Zn(BH4)2, Et3SiH-trifluoroacetic acid, pyridine-BH3,phenylsilane-dibutyltin dichloride, or the corresponding polymerbound-NaBH₄, polymer bound-NaBH₃CN, polymer bound-NaB(OAc)₃H, or anyreducing agent (e.g., hydrogenation, Pd(OAc)₂/potassium formate,Pd/C/H₂) that is known in the literature for reducing the imine bond tothe corresponding amine in an appropriate solvent, such asdichloroethane, chloroform, 2-methoxyethyl ether, dichloroethane, DMF,THF, MeOH, ethanol, about iso-propanol, t-butanol or toluene, at atemperature between room temperature to reflux, preferably at about roomtemperature to about 65° C.

R⁶ of halo group may be generated by reacting the starting materialwherein R⁶ is H with NBS, NCS, or SO₂C₁₂, I₂ in an appropriate solventsuch as methylene chloride, or chloroform. The halo group may bereplaced with another group using methods known in the art of organicchemistry, such as halogen-metal exchange, followed by quenching with anelectrophile, or using typical Suzuki coupling conditions employing acatalyst such as palladium complex liketetrakis(triphenylphosphine)-palladium with sodium carbonate as a basein a suitable solvent such as THF, DME, ethanol and a boronic acid.

The starting materials used in the procedures of the above Schemes, thesyntheses of which are not described above, are either commerciallyavailable, known in the art or readily obtainable from known compoundsusing methods that will be apparent to those skilled in the art.

In the compounds described hereinabove, it is preferred that the carbonattached to the R³ is in the S-configuration. This embodiment isprepared from starting material in which the carbon atom attached to theR³ substituent is in the S configuration. The stereochemistry is derivedfrom the utilization of the L-amino acid. Since during the synthesis, nosubstitution occurs at this asymmetric carbon, the stereochemicalconfiguration is maintained throughout the synthesis to the finalproduct.

The compounds of Formula I, and the intermediates shown in the abovereaction schemes, may be isolated and purified by conventionalprocedures, such as recrystallization or chromatographic separation,such as on silica gel, either with an ethyl acetate/hexane elutiongradient, a methylene chloride/methanol elution gradient, or achloroform/methanol elution gradient. Alternatively, a reverse phasepreparative HPLC or chiral HPLC separation technique may be used.

In each of the reactions discussed or illustrated above, pressure is notcritical unless otherwise indicated. Pressures from about 0.5atmospheres to about 5 atmospheres are generally acceptable, and ambientpressure, i.e., about 1 atmosphere, is preferred as a matter ofconvenience.

Pharmaceutically acceptable salts of the compounds of Formula I may beprepared in a conventional manner by treating a solution or suspensionof the corresponding free base or acid with one chemical equivalent of apharmaceutically acceptable acid or base. Conventional concentration orcrystallization techniques may be employed to isolate the salts.Suitable acids, include, but are not limited to, acetic, lactic,succinic, maleic, tartaric, citric, gluconic, ascorbic, benzoic,cinnamic, fumaric, sulfuric, phosphoric, hydrochloric, hydrobromic,hydroiodic, sulfamic, sulfonic acids such as methanesulfonic, benzenesulfonic, p-toluenesulfonic and related acids. Suitable bases include,but are not limited to, sodium, potassium and calcium.

A compound of the Formula I of the present invention may be administeredto mammals via either the oral, parenteral (such as subcutaneous,intravenous, intramuscular, intrasternal and infusion techniques),rectal, intranasal, topical or transdermal (e.g., through the use of apatch) routes. In general, these compounds are most desirablyadministered in doses ranging from about 0.1 mg to about 500 mg per day,in single or divided doses (i.e., from 1 to 4 doses per day), althoughvariations will necessarily occur depending upon the species, weight,age and condition of the subject being treated, as well as theparticular route of administration chosen. However, a dosage level thatis in the range of about 0.1 mg/kg to about 5 gm/kg body weight per day,preferably from about 0.1 mg/kg to about 100 mg/kg body weight per day,is most desirably employed. Nevertheless, variations may occur dependingupon the species of animal being treated and its individual response tosaid medicament, as well as on the type of pharmaceutical formulationchosen and the time period and interval at which such administration iscarried out. In some instances, dosage levels below the lower limit ofthe aforesaid range may be more than adequate, while in other casesstill larger doses may be employed without causing any harmful sideeffects, provided that such higher dosage levels are first divided intoseveral small doses for administration throughout the day.

A compound of the Formula I of the present invention may be administeredalone or in combination with pharmaceutically acceptable carriers ordiluents by either of the routes previously indicated, and suchadministration may be carried out in single or multiple doses. Suitablepharmaceutical carriers include solid diluents or fillers, sterileaqueous media and various non-toxic organic solvents, etc. Thepharmaceutical compositions formed by combining a compound of theFormula I, or a pharmaceutically acceptable salt thereof, with apharmaceutically acceptable inert carrier, can then be readilyadministered in a variety of dosage forms such as tablets, capsules,lozenges, troches, hard candies, powders, sprays, creams, salves,suppositories, jellies, gels, pastes, lotions, ointments, aqueoussuspensions, injectable solutions, elixirs, syrups, and the like.Moreover, oral pharmaceutical compositions may be suitably sweetenedand/or flavored.

For oral administration, tablets containing various excipients such asmicrocrystalline cellulose, sodium citrate, calcium carbonate, dicalciumphosphate and glycine may be employed along with various disintegrantssuch as starch (preferably corn, potato or tapioca starch),methylcellulose, alginic acid and certain complex silicates, togetherwith granulation binders such as polyvinylpyrrolidone, sucrose, gelatinand acacia. Additionally, lubricating agents such as magnesium stearate,sodium lauryl sulfate and talc are often useful for tabletting purposes.Solid compositions of a similar type may also be employed as fillers ingelatin capsules. Preferred materials in this connection include lactoseor milk sugar as well as high molecular weight polyethylene glycols.When aqueous suspensions and/or elixirs are desired for oraladministration, the active ingredient may be combined with varioussweetening or flavoring agents, coloring matter or dyes, and, if sodesired, emulsifying and/or suspending agents as well, together withsuch diluents as water, ethanol, propylene glycol, glycerin and variouslike combinations thereof.

For parenteral administration, solutions containing a compound of theFormula I of the present invention in either sesame or peanut oil or inaqueous propylene glycol may be employed. The aqueous solutions shouldbe suitably buffered (preferably pH greater than 8) if necessary and theliquid diluent first rendered isotonic with sufficient saline orglucose. These aqueous solutions are suitable for intravenous injectionpurposes. The oily solutions are suitable for intraarticular,intramuscular and subcutaneous injection purposes. The preparation ofall these solutions under sterile conditions is readily accomplished bystandard pharmaceutical techniques well known to those skilled in theart.

The compounds of Formula I of the present invention are useful ininhibiting Aβ-peptide production (thus, gamma-secretase activity) inmammals, and therefore they are able to function as therapeutic agentsin the treatment of the aforementioned disorders and diseases in anafflicted mammal.

The ability of compounds of the Formula I of this invention, and theirpharmaceutically acceptable salts, to inhibit Aβ-peptide production(thus, gamma-secretase activity) may be determined using biologicalassays known to those of ordinary skill in the art, for example theassays described below.

The activity of compounds of the Formula I of the present invention ininhibiting gamma-secretase activity was determined in a solubilizedmembrane preparation generally according to the description provided inMcLendon et al. Cell-free assays for γ-secretase activity, The FASEBJournal (Vol. 14, December 2000, pp. 2383-2386). Using such assay,compounds of the present invention were determined to have an IC₅₀activity for inhibiting gamma-secretase activity of less than about 100micromolar.

The following Examples illustrate the present invention. It is to beunderstood, however, that the invention, as fully described herein andas recited in the claims, is not intended to be limited by the detailsof the following Examples.

EXPERIMENTAL PROCEDURES Example 12-12-[2-(3,5-Difluoro-phenyl)-acetylamino]-butyrylamino-4-trifluoromethyl-oxazole)-5-carboxylicAcid Ethyl Ester

A mixture of a 2-[2-(3,5-difluoro-phenyl)-acetylamino]-butyric acid (54mg, 0.2 mmol), 2-amino-4-trifluoromethyl-oxazole-5-carboxylic acid ethylester (45 mg, 0.2 mmol.), HBOT (32 mg, 0.24 mmol), EDC. HCl (58 mg, 0.3mmol) and a trimethylamine (0.11 ml, 0.8 mmol) in methylene chloride wasstirred at room temperature until disappearance of starting material.The mixture was quenched with water and extracted with methylenechloride. The organic layer was washed with dilute HCl, brine, driedover sodium sulfate and the solvent was removed at reduced pressure toprovide the title compound. 1H NMR (CD₃OD) d 6.9 (m, 2H), 6.8(m,1H),4.4(m,1H), 4.4(q,2H), 3.6(s,2H), 1.9(m,1H), 1.8(m,1 H), 1.35(t,3H),1.0(t, 3H) ppm. M+1=463.36.

Example 2 2-[2-(3-Phenoxy-phenyl)-acetylamino]-pentanoic acid(5-benzoyl-oxazol-2-yl)-amide

A mixture of 2-[2-(3-phenoxy-phenyl)-acetylamino]-pentanoic acid (65 mg,0.2 mmol), (2-Amino-oxazol-5-yl)-phenyl-methanone (38 mg, 0.2 mmol.),HBOT (32 mg, 0.24 mmol), EDC. HCl (58 mg, 0.3 mmol) and a trimethylamine(0.11 ml, 0.8 mmol) in methylene chloride was stirred at roomtemperature until disappearance of starting material. The mixture wasquenched with water and extracted with methylene chloride. The organiclayer was washed with dilute HCl, brine, dried over sodium sulfate andthe solvent was removed at reduced pressure to provide the titlecompound, LC-MS M+1=498.5.

The following examples were prepared by the method analogous to that inexample 1 or 2 starting with an appropriate acid and an appropriate2-amino-oxazole.

Example 3 2-[2-(3-Phenoxy-phenyl)-acetylamino]-pentanoic acid(5-acetyl-oxazol-2-yl)-amide

M+1=436.5.

Example 4 2-[2-(3-Phenoxy-phenyl)-acetylamino]-pentanoic acid(5-phenyl-oxazol-2-yl)-amide

M+1=470.5.

Example 5 2-[2-(3-Phenoxy-phenyl)-acetylamino]-pentanoic acid (4.5-dimethyl-oxazol-2-yl)-amide

M+1=422.5.

Example 6 2-[2-(3-Phenoxy-phenyl)-acetylamino]-pentanoic acid[5-(thiophene-2-carbonyl)-oxazol-2-yl]-amide

M+1=504.4.

Example 7 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(hydroxy-phenyl-methyl)-4-methyl-oxazol-2-yl]-amide

M+1=458.6.

Example 8 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid(5-acetyl-oxazol-2-yl)-amide

M+1=380.2.

Example 9 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(4-fluoro-benzoyl)-oxazol-2-yl]-amide

M+1=460.1.

Example 10 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(3-bromo-benzoyl)-oxazol-2-yl]-amide

M+1=521.9.

Example 11 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid(5-acetyl-oxazol-2-yl)-amide Example 122-[2-[2-(3,5-Difluoro-phenyl)-acetylamino]-Pentanoylamino-4-trifluoromethyl-oxazole-5-carboxylicacid methyl ester

M+1=464.1

Example 13 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid(5-hydroxymethyl-4-trifluoromethyl-oxazol-2-yl)-amide

A mixture of2-{2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoylamino}-4-trifluoromethyl-oxazole-5-carboxylicacid ethyl ester (150 mg, 0.31 mmol) and sodium borohydride (150 mg,3.947 mmol) in 3 ml methanol was stirred at room temperature for 10 min.The mixture was quenched with water and extracted with ethyl acetate.The organic layer was separated, dried and concentrated and the residuewas purified by preparative HPLC to give the title compound as a whitesolid. APCl M+1=436.1.

Example 14 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(1-hydroxy-ethyl)-oxazol-2-yl]-amide

To a solution of 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid(5-acetyl-oxazol-2-yl)-amide (130 mg, 0.34 mmol) in a mixture of MeOH (5ml) and THF (5 mL) was added NaBH4 (130 mg, 3. 9 mmol) at roomtemperature. After stirring for 10 min, the mixture was concentrated toa small volume, quenched with water and extracted with methylenechloride. The organic layer was separated, dried and concentrated togive 131 mg of the title compound as a colorless oil. LC-MS, RT=1.7 min,M+1=382.2, M−1=380.2.

Example 15 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid{5-[1-(3-methyl-butylamino)-ethyl]-oxazol-2-yl}-amide Hydrogen Chloride

To a mixture of 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid(5-acetyl-oxazol-2-yl)-amide (100 mg, 0.26 mmol), isoamylamine (0.2 ml),NaOAc, Na2SO4, AcOH(0.1 ml) in methylene chloride was stirred at roomtemperature for 2 hr. NaBH3CN (80 mg, 3.4 mmol) was added. The mixturewas heated at 40-45° C. until all starting material was consumed andproduct was formed. The mixture was quenched with dilute NaOH, extractedwith methylene chloride, then extracted with ethyl acetate. The combinedorganic layers were dried over Na₂SO₄ (anhydrous), filtered, andconcentrated to give 120 mg of the title compound. The crude materialwas purified by silica gel column chromatography using 1% to 5% MeOH inmethylene chloride as eluent to give the desired product that wasprepared to the corresponding HCl salt with HCl in dioxane. The salt wastitrated with hexane to give the title compound as a white solid. LC-MS,RT=1.3 min, M−1=449.2.

The following examples were prepared by methods analogous to thosedescribed in Example 15 above, starting with an appropriate ketone andan appropriate amine.

Example 16 2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic Acid(5-acetyl-oxazol-2-yl)-amide

M+1=340.4, M−1=338.4.

Example 17 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic Acid{5-[1-(3,3-dimethyl-butylamino)-ethyl]-oxazol-2-yl]-amide

M+1=465.5, M−1=463.5.

Example 18 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic Acid[5-[1-(2,2,2-trifluoro-ethylamino)-ethyl]-oxazol-2-yl}-amide

M+1=463.4, M−1=461.4.

Example 19 2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic Acid[5-[1-(3,3-dimethyl-butylamino)-ethyl]-oxazol-2-yl]-amide

M+1=425.6, M−1=423.5.

Example 20 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic Acid{5-(1-(3-methyl-butylamino)-ethyl]-oxazol-2-yl}-amide

M+1=451.5, M−1=449.5.

Example 21 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(1-isobutylamino-ethyl)-oxazol-2-yl]-amide

M−1=435.5.

Preparation of Intermediate2-[2-(3-phenoxy-phenyl)-acetylamino]-pentanoic Acid

A mixture of (3-Phenoxy-phenyl)-acetic acid (10.00 g, 0.0438 mol),2-amino-pentanoic acid methyl ester (7.34 g, 0.0438 mol.), HBOT (6.20 g,0.046 mol), EDC. HCl (12.59 g, 0.067 mol) and a trimethylamine (30.45ml, 0.22 mol) in methylene chloride (150 ml) was stirred at roomtemperature overnight. The mixture was quenched with water and extractedwith methylene chloride. The organic layer was washed with 1N HCl, thenbrine, dried over sodium sulfate and the solvent was removed at reducedpressure to provide 13.99 g of (3-phenoxy-phenyl)-acetic acid methylester as a thick oil, LC-MS M+1=342.

A mixture of (3-phenoxy-phenyl)-acetic acid methyl ester (7 g, 0.0205mol) and 1N NaOH (61.5 ml, 0.0651 mol) in 120 ml of methanol was stirredat room temperature overnight. The mixture was concentrated to a lowvolume and the residue was diluted with HCl to pH around 3.4 andextracted twice with ethyl acetate. The organic layer was separated,dried over MgSO4, filtered. The filtrate was concentrated to dryness togive 5.86 g of 2-[2-(3-phenoxy-phenyl)-acetylamino]-pentanoic acid as awhite solid, LC-MS M+1=328.

Example 22 2-[2-(5-Phenoxy-3-pyridyl)-acetylamino]-pentanoic Acid(5-benzoyl-oxazol-2-yl)-amide Example 232-[2-(5-Phenoxy-3-pyridyl)-acetylamino]-pentanoic Acid(5-acetyl-oxazol-2-yl)-amide Example 232-[2-(5-Phenoxy-3-pyridyl)-acetylamino]-pentanoic Acid(5-phenyl-oxazol-2-yl)-amide Example 242-[2-(3,5-Difluoro-phenyl)-acetylamino]-propanoic Acid[4-(phenyl)-5-(ethyl)-oxazol-2-yl]-amide Example 252-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic Acid [5-carboxylicAcid Ethyl Ester-oxazol-2-yl]-amide Example 262-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic Acid[5-(2-hyroxypropyl)-oxazol-2-yl]-amide Example 272-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid{5-(carboxy)-oxazol-2-yl}-amide Example 282-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid{5-(phenyl)-oxazol-2-yl}-amide Example 292-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [(5-carboxylicAcid Ethyl Ester-5-trifluoromethyl)oxazol-2-yl]-amide

The activity of the compounds described in examples 1, 5, 6, 7, 8, 9,10, 11, 12, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,and 29 in inhibiting gamma-secretase activity was determined in asolubilized membrane preparation generally according to the descriptionprovided in McLendon et al. Cell-free assays for γ-secretase activity,The FASEB Journal (Vol. 14, December 2000, pp. 2383-2386). At least 65%exhibited IC₅₀ values less than 1000 nM. A subgroup of these compoundsexhibited preferable IC₅₀ values of less than 300 nM. A further subgroupof these compounds exhibited more preferable IC₅₀ values of less than100 nM. A still further subgroup of these compounds exhibited mostpreferable IC₅₀ values of less than 20 nM.

1. Compounds of the formula

wherein Z is selected from —C(═O)CHR¹R², —C(═S)CHR¹R², —(C═NR⁸)CHR¹R²,—C(═O)C(═O)R¹ and —S(O)₂—R¹; R¹ is selected from -C₁-C₂₀ alkyl, -C₂-C₂₀alkenyl, -C₂-C₂₀ alkynyl, -C₁-C₂₀ alkoxy, -C₂-C₂₀ alkenoxy, -C₂-C₂₀alkynoxy, -C₃-C₂₀ cycloalkyl, -C₄-C₂₀ cycloalkenyl, (C₁₀-C₂₀)bi- ortricycloalkyl, (C₁₀-C₂₀)bi- or tricycloalkenyl, (4-20 membered)heterocycloalkyl, -C₆-C₂₀ aryl and (5-20 membered) heteroaryl; whereinR¹ is optionally independently substituted with from one to six fluorineatoms or with from one to three substituents independently selected fromthe group R^(1a); R^(1a) is in each instance independently selected from—OH, -C₁-C₁₂ alkyl, -C₂-C₁₂ alkenyl, -C₂-C₁₂ alkynyl, -C₁-C₆ alkoxy,-C₂-C₆ alkenoxy, -C₂-C₆ alkynoxy, —F, —Cl, —Br, —I, —CN, —NO₂, —NR⁹R¹⁰,—C(═O)NR⁹R¹⁰, —S(O)_(n)—NR⁹R¹⁰, —C(═O)R¹¹, —S(O)_(n)—R¹¹, —C(═O)OR₁₂,-C₃-C₁₅ cycloalkyl, -C₄-C₁₅ cycloalkenyl, -(C₅-C₁₁)bi- or tricycloalkyl,-(C₇-C₁₁)bi- or tricycloalkenyl, -(4-20 membered) heterocycloalkyl,-C₆-C₁₅ aryl, -(5-15 membered) heteroaryl, -C₆-C₁₅ aryloxy and -(5-15membered) heteroaryloxy, wherein said cycloalkyl, cycloalkenyl, bi- ortricycloalkyl, bi- or tricycloalkenyl, heterocycloalkyl, aryl,heteroaryl, aryloxy and heteroaryloxy are each optionally independentlysubstituted with from one to three substituents independently selectedfrom the group R^(1b); R^(1b) is in each instance independently selectedfrom —OH, -C₁-C₆ alkyl, -C₂-C₆ alkenyl, -C₂-C₆ alkynyl, -C₁-C₆ alkoxy,-C₂-C₆ alkenoxy, -C₂-C₆ alkynoxy, -C₁-C₆ hydroxyalkyl, —F, —Cl, —Br, —I,—CN, —NO₂, —NR⁹R¹⁰, —C(═O)NR⁹R¹⁰, —C(═O)R¹¹, —S(O)_(n)NR⁹R¹⁰,—S(O)_(n)—R¹¹, -C₆-C₁₅ aryloxy and -(5-15 membered) heteroaryloxy,wherein said alkyl, alkenyl and alkynyl are each optionallyindependently substituted with from one to six fluorine atoms or withfrom one to two substituents independently selected from -C₁-C₄ alkoxy,or with a hydroxy group; R⁹ and R¹⁰ are in each instance eachindependently selected from —H, -C₁-C₁₂ alkyl, -C₂-C₁₂ alkenyl, -C₂-C₁₂alkynyl, —CF₃, —C(═O)R¹¹, —S(O)_(n)—R¹¹, —C(═O)OR¹², —C(═O)NR¹¹R¹²,—S(O)_(n)—NR¹¹R¹², (C_(zero)-C₄ alkylene)-(C₃-C₂₀ cycloalkyl),(C_(zero)-C₄ alkylene)-(C₄-C₈ cycloalkenyl), -(C_(zero)-C₄alkylene)-((C₅-C₁₁)bi- or tricycloalkyl), (C_(zero)-C₄alkylene)-((C₇-C₁₁)bi- or tricycloalkenyl), -(C_(zero)-C₄alkylene)-((5-10 membered) heterocycloalkyl), (C_(zero)-C₄alkylene)-(C₆-C₁₀ aryl) and -(C_(zero)-C₄ alkylene)-((5-10 membered)heteroaryl), wherein said alkyl, alkenyl and alkynyl are each optionallyindependently substituted with from one to six fluorine atoms or withfrom one to two substituents independently selected from -C₁-C₄ alkoxy,or with a hydroxy group, and wherein said cycloalkyl, cycloalkenyl,bi-or tricycloalkyl, bi- or tricycloalkenyl, heterocycloalkyl, aryl andheteroaryl are each optionally independently substituted with from oneto three substituents independently selected from —OH, -C₁-C₁₂ alkyl,-C₂-C₁₂ alkenyl, -C₂-C₁₂ alkynyl, -C₁-C₆ alkoxy, -C₂-C₆ alkenoxy, -C₂-C₆alkynoxy, -C₁-C₆ hydroxyalkyl, —F, —Cl, —Br, —I, —CN, —NO₂, —CF₃, —NH₂,—C(═O)NH₂, —S(O)_(n)—NH₂, —C(═O)H and —C(═O)OH, wherein said alkyl,alkenyl and alkynyl substituents are each optionally independentlyfurther substituted with from one to six fluorine atoms or with from oneto two substituents independently selected from -C₁-C₄ alkoxy, or with ahydroxy group; or NR⁹R¹⁰ may in each instance independently optionallyform a heterocycloalkyl moiety of from four to ten ring members, saidheterocycloalkyl moiety optionally containing one to two furtherheteroatoms independently selected from N, O and S, and optionallycontaining from one to three double bonds, wherein the carbon atoms ofthe heterocycloalkyl moiety of NR⁹R¹⁰ are optionally independentlysubstituted with from one to three substituents independently selectedfrom —OH, -C₁-C₁₂ alkyl, -C₂-C₁₂ alkenyl, -C₂-C₁₂ alkynyl, -C₁-C₆alkoxy, -C₂-C₆ alkenoxy, -C₂-C₆ alkynoxy, —F, —Cl, —Br, —I, —CF₃, —NH₂,—C(═O)NH₂, —S(O)_(n)—NH₂, —C(═O)R¹¹, —S(O)_(n)—R¹¹, (C_(zero)-C₄alkylene)-(C₆-C₁₀ aryl), (C_(zero)-C₄ alkylene)-((5-10 memberedheteroaryl), (C_(zero)-C₄ alkylene)-(C₆-C₁₀ cycloalkyl) and (C_(zero)-C₄alkylene)-((5-10 membered) heterocycloalkyl, and wherein the(C_(zero)-C₄ alkylene)-((5-10 membered) heterocycloalkyl) substituentand the nitrogen atoms of said heterocycloalkyl moiety of NR⁹R¹⁰ areeach optionally independently substituted with one substituentindependently selected from -C₁-C₁₂ alkyl, -C₂-C₁₂ alkenyl, -C₂-C₁₂alkynyl, —C(═O)NH₂, —S(O)_(n)—NH₂, C(═O)R¹¹, —S(O)_(n)—R¹¹, (C_(zero)-C₄alkylene)-(C₆-C₁₀ aryl), (C_(zero)-C₄ alkylene)-((5-10 membered)heteroaryl), (C_(zero)-C₄ alkylene)-(C₆-C₁₀ cycloalkyl) and (C_(zero)-C₄alkylene)-((5-10 membered) heterocycloalkyl), and wherein said alkyl,alkenyl and alkynyl substituents are each optionally independentlyfurther substituted with from one to six fluorine atoms, or with fromone to two substituents independently selected from -C₁-C₄ alkoxy, orwith a hydroxy group; R¹¹ and R¹² are in each instance eachindependently selected from -C₁-C₁₅ alkyl (branched or straight chain),-C₂-C₆ alkenyl, -C₂-C₆ alkynyl, -(C_(zero)-C₄ alkylene)-(C₃-C₁₅cycloalkyl), -(C_(zero)-C₄ alkylene)-(C₄-C₈ cycloalkenyl), -(C_(zero)-C₄alkylene)-((C₅-C₁₁)bi- or tricycloalkyl), -(C_(zero)-C₄alkylene)-((C₇-C₁l)bi- or tricycloalkenyl), -(C_(zero)-C₄alkylene)-(C₆-C₁₅ aryl), -(C_(zero)-C₄ alkylene)-((5-15 membered)heterocycloalkyl) and -(C_(zero)-C₄ alkylene)-((5-15 membered)heteroaryl); wherein R¹¹ and R¹² are each optionally independentlysubstituted with from one to six fluorine atoms or with from one tothree substituents independently selected from group R^(1b), and whereinsaid alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bi-ortricycloalkyl, bi- or tricycloalkenyl, heterocycloalkyl, aryl andheteroaryl are each optionally independently substituted with from oneto three substituents independently selected from —OH, -C₁-C₁₂ alkyl,-C₂-C₁₂ alkenyl, -C₂-C₁₂ alkynyl, -C₁-C₆ alkoxy, -C₂-C₆ alkenoxy, -C₂-C₆alkynoxy, -C₁-C₆ hydroxyalkyl, —F, —Cl, —Br, —I, —CN, —NO₂, —CF₃, —NH₂,—NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl),—C(═O)N(C₁-C₆ alkyl)₂, —NR⁹R¹⁰, —C(═O)NR⁹R¹¹ ⁰, —C(═O)R¹¹,—S(O)_(n)NR⁹R¹⁰, —S(O)_(n)—R¹¹, -C₆-C₁₅ aryloxy and -(5-15 membered)heteroaryloxy, —SO₂NH₂, —SO₂NH(C₁-C₆ alkyl), —SO₂N(C₁-C₆ alkyl)₂,—C(═O)H, —C(═O)OH and —C(═O)O(C₁-C₆ alkyl), wherein said alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkynyl substituents are each optionallyindependently further substituted with from one to six fluorine atoms orwith from one to two substituents independently selected from -C₁-C₄alkoxy, or with a hydroxy group; NR¹¹R¹² may in each instanceindependently optionally form a heterocycloalkyl moiety of from four toten ring members, said heterocycloalkyl moiety optionally containing oneto two further heteroatoms independently selected from N, O and S, andoptionally containing from one to three double bonds, wherein the carbonatoms of said heterocycloalkyl moiety of NR⁹R¹⁰ are optionallyindependently substituted with from one to three substituentsindependently selected from —OH, -C₁-C₁₂ alkyl, -C₂-C₁₂ alkenyl, -C₂-C₁₂alkynyl, -C₁-C₆ alkoxy, -C₂-C₆ alkenoxy, -C₂-C₆ alkynoxy, -C₁-C₆hydroxyalkyl, —F, —Cl, —Br, —I, —CN, —NO₂, —CF₃, —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆alkyl)₂, —SO₂NH₂, —SO₂NH(C₁-C₆ alkyl), —SO₂N(C₁-C₆ alkyl)₂, —C(═O)H,—C(═O)OH and —C(═O)O(C₁-C₆ alkyl), wherein said alkyl, alkenyl andalkynyl substituents are each optionally independently furthersubstituted with from one to six fluorine atoms or with from one to twosubstituents independently selected from -C₁-C₄ alkoxy, or with ahydroxy group; R² is selected from —H, —OH, —NH₂, —CH₂OH, —OC(═O)CH₃,—C(CH₃)₂OH, —C(CH₃)(CH₂CH₃)(OH), —C(OH)(C_(zero)-C₄ alkyl)(C_(zero)-C₄alkyl), —OC(═O)R⁴ and —OC(═O)OR⁴, wherein said —OC(═O)R⁴ and —OC(═O)OR⁴may optionally be a prodrug of the corresponding OH of R²; R⁴ isselected from -C₁-C₄ alkyl, —CH(OH)(C₁-C₄ alkyl), —CH(OH)(C₅-C₆ aryl),—CH(OH)((5-6 membered) heteroaryl), —CH(OH)(C₅-C₆ membered cycloalkyl),—CH(OH)((5-6 membered) heterocycloalkyl); R³ is selected from -C₁-C₆alkyl, -C₂-C₆ alkenyl, -C₂-C₆ alkynyl and -(C_(zero)-C₄ alkylene)-(C₃-C₆cycloalkyl), wherein when R³ is alkyl, alkenyl, allyl, or alkynyl, R³ isoptionally independently substituted with a substituent independentlyselected from -C₁-C₄ alkoxy, —OH and —S(C₁-C₄ alkyl); R⁵ is selectedfrom —H, -C₁-C₄ alkyl, -C₂-C₄ alkenyl, -C₂-C₄ alkynyl, —C(═O)(C₁-C₄alkyl), -C₆-C₁₀ aryl, -(5-20 membered) heteroaryl, —S(O)_(n)-(C₆-C₁₀aryl), —S(O)_(n)-((5-20 membered) heteroaryl), —S(O)_(n)—CH₂-(C₆-C₂₀aryl) and —S(O)_(n)—CH₂-((5-20 membered) heteroaryl); R⁶ is selectedfrom —H, -C₁-C₄ alkyl, -C₂-C₄ alkenyl, -C₂-C₄ alkynyl, —F, —Cl, —Br, —I,—CN, —CF₃, —C(═O)NR⁹R¹⁰, —S(O)_(n)—NR⁹R¹⁰, —C(═O)R¹¹, —S(O)_(n)—R¹¹,—C(═O)OR¹², -(C_(zero)-C₄ alkylene)-C(═O)OR¹², -C₃-C₂₀ cycloalkyl,-C₄-C₂₀ cycloalkenyl and -C₆-C₁₀ aryl, wherein said alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl and aryl are each optionallyindependently substituted with from one to three substituentsindependently selected from the group R^(1b); R⁷ is selected from —H,-C₁-C₂₀ alkyl, -C₂-C₂₀ alkenyl, -C₂-C₂₀ alkynyl, -C₁-C₂₀ alkoxy, -C₂-C₂₀alkenoxy, -C₂-C₂₀ alkynoxy, —F, —Cl, —Br, —I, —CN, —NO₂, —OH, —CF₃,—NR⁹R¹⁰, —C(═O)NR⁹R¹⁰, —C(═O)R¹¹, —C(═O)OR ², -C₃-C₁₅ cycloalkyl,(C_(zero)-C₄ alkylene)(C₃-C₂₀ cycloalkyl), -(3-15 membered)heterocycloalkyl, -C₆-C₁₅ aryl, -(5-15 membered) heteroaryl, —CHO,C_(zero)-C₄ alkylene)-(C₃-C₂₀ cycloalkyl), C_(zero)-C₄ alkylene)-(C₄-C₂₀cycloalkenyl), C_(zero)-C₄ alkylene)-((C₁₀-C₂₀)bi- or tricycloalkyl),-(C_(zero)-C₄ alkylene)-((C₁₀-C₂₀)bi- or tricycloalkenyl), C_(zero)-C₄alkylene)-((3-20 membered) heterocycloalkyl), C_(zero)-C₄alkylene)-(C₆-C₁₅ aryl) and C_(zero)-C₄ alkylene)-((5-15 membered)heteroaryl), —C(═O)(C₁-C₁₅ alkyl), —C(═O)((5-15 membered)heterocycloalkyl), —C(═O)((5-15 membered) heteroaryl), —C(═O)(C₅-C₁₅cycloalkyl), —C(═O)O(C₁-C₈ alkyl), —C(═O)N(C₁-C₁₀ alkyl)(C₁-C₁₀ alkyl),C(═O)N(C_(zero)-C₁₀ alkyl)(C₆-C₁₀ aryl), —C(═O)N(C_(zero)-C₁₀alkyl)((5-10 membered) heteroaryl), —C(═O)N(C_(zero)-C₁₀ alkyl)((5-10membered) heterocycloalkyl), —C(═O)N(C_(zero)-C₁₀ alkyl)(C₅-C₁₀cycloalkyl), —S(O)_(n)—R¹¹, —S(O)_(n)-(C₁-C₆ alkyl), —S(O)_(n)-(C₃-C₈cycloalkyl), —S(O)_(n)-alkyl, —S(O)_(n)-cycloalkyl, —S(O)_(n)-(6 to 14membered) aryl, —S(O)_(n)-(5 to 14 membered) heteroaryl, -(C_(zero)-C₄alkylene)(4-15 membered) heterocycloalkyl, wherein said heterocycloalkyloptionally contains from one to four double or triple bonds, wherein R⁷is optionally substituted with from one to six fluorine atoms or withfrom one to three substituents independently selected from the groupR^(1a); or alternatively R⁷ is selected from —H, -C₁-C₁₂ alkyl, -C₂-C₁₂alkenyl, -C₂-C₁₂ alkynyl, -C₁-C₂₀ alkoxy, —F, —Cl, —Br, —I, —CN, —NO₂,-C₃-C₁₅ cycloalkyl, -(C_(zero)-C₄ alkylene)(C₃-C₁₅ cycloalkyl), -(3-15membered) heterocycloalkyl, -C₆-C₁₅ aryl, -(5-15 membered) heteroaryl,—CHO, —C(═O)(C₁-C₁₅ alkyl), —C(═O)((5-15 membered)heterocycloalkyl),—C(═O)((5-15 membered) heteroaryl), —C(═O)(C₅-C₁₅ cycloalkyl),—C(═O)O(C₁-C₈ alkyl), —C(═O)N(C₁-C₁₀ alkyl)(C₁-C₁₀ alkyl),C(═O)N(C_(zero)-C₁₀ alkyl)(C₆-C₁₀ aryl), —C(═O)N(C_(zero)-C₁₀alkyl)((5-10 membered) heteroaryl), —C(═O)N(C_(zero)-C₁₀ alkyl)((5-10membered) heterocycloalkyl), —C(═O)N(C_(zero)-C₁₀ alkyl)(C₅-C₁₀cycloalkyl), —S(O)_(n)—(C₁-C₆ alkyl), —S(O)_(n)-(C₃-C₈ cycloalkyl),—S(O)_(n)-alkyl, —S(O)_(n)-cycloalkyl, —S(O)_(n)-(6 to 14 membered)aryl, —S(O)_(n)-(5 to 14 membered) heteroaryl, -(C_(zero)-C₄alkylene)(4-15 membered) heterocycloalkyl, wherein said alkyl, alkenyl,alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl areeach optionally independently substituted with from one to threesubstituents independently selected from —F, —Cl, —Br, —I, —OH, -C₁-C₁₀alkyl, -C₂-C₁₀ alkenyl, -C₁-C₁₀ alkoxy, -C₂-C₁₀ alkenoxy, -C₂-C₁₀alkynoxy, —NR⁹R¹⁰, (C₁-C₁₁ alkyl)—NR⁹R¹⁰, —C(═O)R¹¹, —S(O)_(n)—R¹¹,—C(═O)OR¹², —C(═O)NR⁹R¹⁰, —S(O)_(n)—NR⁹R¹⁰-C₃-C₁₅ cycloalkyl, -(4-15membered) heterocycloalkyl, -C₆-C₁₅ aryl, -(5-15 membered) heteroaryl,(5-15 membered) heterocycloalkoxy, -C₆-C₁₂ aryloxy and (6-12 membered)heteroaryloxy; or R⁶ and R⁷ may together with the carbon atoms to whichthey are respectively attached optionally form a five to fourteenmembered cycloalkyl ring, a five to fourteen membered heterocycloalkylring, a ten to fourteen membered bicycloalkyl ring or a ten to fourteenmembered bicycloheteroalkyl ring fused to the oxazole ring in thecompound of Formula I, wherein from one to three members of saidheterocycloalkyl ring or said bicycloheteroalkyl ring are selected fromN, O and S, and wherein said cycloalkyl, heterocycloalkyl, bicycloalkylor bicylcoheteroalkyl ring optionally contains from one to three doublebonds; and R⁸ is selected from —H and -C₁-C₆ alkyl; or, when Z is—C(═NR⁸)CHR¹R², R⁸ and R¹ may together with the nitrogen and carbonatoms to which they are respectively attached optionally form a five tofourteen membered heteroaryl ring or a five to eight memberedheterocycloalkyl ring, wherein said heteroaryl or heterocycloalkyl ringoptionally contains from one to two further heteroatoms selected from N,O and S, and wherein said heterocycloalkyl ring optionally contains fromone to three double bonds, and wherein said heteroaryl orheterocycloalkyl ring is optionally substituted with from one to threesubstituents independently selected from the group R^(1b); n is in eachinstance an integer independently selected from 0, 1, and 2; and thepharmaceutically acceptable salts of such compounds.
 2. The compounds ofclaim 1 wherein the stereochemistry of the R³ substituent is as shown informula I-A below.


3. The compounds of claim 1 claim wherein Z is —C(═O)CHR¹R², R² is —H,—OH, or OC(═O)CH₃.
 4. The compounds of claim 2 wherein Z is—C(═O)CHR¹R², R² is —H, —OH, or OC(═O)CH₃.
 5. The compounds of claim 1wherein Z is selected from the group consisting of —C(═O)C(═O)R¹ and—SO₂R¹.
 6. The compounds of claim 2 wherein Z is selected from the groupconsisting of —C(═O)C(═O)R¹ and —SO₂R¹.
 7. The compounds of claim 1wherein R¹ is selected from the group consisting of -C₁-C₁₀ alkyl,-C₂-C₁₀ alkenyl, -C₃-C₁₀ cycloalkyl, phenyl, thienyl, pyridyl, and-C₃-C₇ cycloalkyl, wherein when R¹ is selected from the group consistingof -C₁-C₁₀ alkyl, -C₂-C₁₀ alkenyl, -C₃-C₁₀ cycloalkyl, phenyl, thienyl,pyridyl, R¹ is optionally independently substituted with from one to twosubstituents independently selected from -C₁-C₄ alkyl, —CF₃, -C₁-C₄alkoxy, —F, —Cl, —Br, phenyl and phenoxy, wherein R¹ optionally containsone or two double or triple bonds, and wherein when R¹ is selected fromthe group consisting of phenyl and pyridyl, R¹ further is optionallyindependently substituted with from one to two substituentsindependently selected from —F, and —Cl.
 8. The compounds of claim 1wherein R² is selected from the group consisting of —H, —OH, —NH₂—OC(═O)CH₃.
 9. The compounds of claim 1 wherein R³ is selected from-C₁-C₄ alkyl, allyl, and —CH₂CH₂SCH₃. The compounds of any precedingclaim wherein R⁵ is H.
 10. The compounds of claim 2 wherein R³ isselected from -C₁-C₄ alkyl, allyl, and —CH₂CH₂SCH₃. The compounds of anypreceding claim wherein R⁵ is H.
 11. The compounds of claim 1 wherein R⁶is selected from the group consisting of —H, —CH₃, —F, —Cl, —Br CF₃, and—C(═O)R¹¹, and R⁷ is selected from the group consisting of -C₁-C₁₂alkyl, -C₂-C₁₂ alkenyl, -C₂-C₁₂ alkynyl, -(C_(zero)-C₄ alkylene)(C₃-C₁₅cycloalkyl), and -(C_(zero)-C₄ alkylene)(4-15 membered)heterocycloalkyl, wherein said alkyl, alkenyl, cycloalkyl andheterocycloalkyl are each optionally independently substituted with froma substituent selected from —OH, -C₁-C₆ alkoxy, -C₂-C₆ alkenoxy, -C₂-C₆alkynoxy and —NR⁹R¹⁰.
 12. The compounds of claim 1 selected from thegroup consisting of2-{2-[2-(3,5-Difluoro-phenyl)-acetylamino]-butyrylamino}-4-trifluoromethyl-oxazole-5-carboxylicacid ethyl ester; 2-[2-(3-Phenoxy-phenyl)-acetylamino]-pentanoic acid(5-benzoyl-oxazol-2-yl)-amide;2-[2-(3-Phenoxy-phenyl)-acetylamino]-pentanoic acid(5-acetyl-oxazol-2-yl)-amide;2-[2-(3-Phenoxy-phenyl)-acetylamino]-pentanoic acid(5-phenyl-oxazol-2-yl)-amide;2-[2-(3-Phenoxy-phenyl)-acetylamino]-pentanoic acid(4,5-dimethyl-oxazol-2-yl)-amide;2-[2-(3-Phenoxy-phenyl)-acetylamino]-pentanoic acid[5-(thiophene-2-carbonyl)-oxazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(hydroxy-phenyl-methyl)-4-methyl-oxazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid(5-acetyl-oxazol-2-yl)-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(4-fluoro-benzoyl)-oxazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(3-bromo-benzoyl)-oxazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid{5-[1-(3-methyl-butylamino)-ethyl]-oxazol-2-yl}-amide;2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid(5-acetyl-oxazol-2-yl)-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid(5-acetyl-oxazol-2-yl)-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(1-hydroxy-ethyl)-oxazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid{5-[1-(3,3-dimethyl-butylamino)-ethyl]-oxazol-2-yl}-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid{5-[1-(2,2,2-trifluoro-ethylamino)-ethyl]-oxazol-2-yl}-amide;2-(2-Hydroxy-3,3-dimethyl-butyrylamino)-pentanoic acid{5-[1-(3,3-dimethyl-butylamino)-ethyl]-oxazol-2-yl}-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid{5-[1-(3-methyl-butylamino)-ethyl]-oxazol-2-yl}-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(1-isobutylamino-ethyl)-oxazol-2-yl]-amide2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid(5-hydroxymethyl-4-trifluoromethyl-oxazol-2-yl)-amide;2-{2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoylamino}-4-trifluoromethyl-oxazole-5-carboxylicacid methyl ester; 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoicacid {5-[1-(3-methyl-butylamino)-ethyl]-oxazol-2-yl}-amide hydrogenchloride; 2-[2-(5-Phenoxy-3-pyridyl)-acetylamino]-pentanoic acid(5-benzoyl-oxazol-2-yl)-amide;2-[2-(5-Phenoxy-3-pyridyl)-acetylamino]-pentanoic acid(5-acetyl-oxazol-2-yl)-amide;2-[2-(5-Phenoxy-3-pyridyl)-acetylamino]-pentanoic acid(5-phenyl-oxazol-2-yl)-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-propanoic acid[4-(phenyl)-5-(ethyl)-oxazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-carboxylicacid ethyl ester-oxazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid[5-(2-hyroxypropyl)-oxazol-2-yl]-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid{5-(carboxy)-oxazol-2-yl}-amide;2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid{5-(phenyl)-oxazol-2-yl}-amide; and2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [(5-carboxylicacid ethyl ester-5-trifluoromethyl)oxazol-2-yl]-amide.
 13. Apharmaceutical composition for inhibiting Aβ-peptide production in amammal, comprising an amount of the compound according to claim 1 or apharmaceutically acceptable salt thereof, that is effective ininhibiting Aβ-production, and a pharmaceutically acceptable carrier. 14A pharmaceutical composition for treating a disease or conditionselected from the group consisting of Alzheimer's disease, hereditarycerebral hemorrhage with amyloidosis, cerebral amyloid angiopathy, aprion-mediated disease, inclusion body myositis, stroke, multiplesclerosis and Down's Syndrome in a mammal, comprising an amount of thecompound according to claim 1 or a pharmaceutically acceptable saltthereof, that is effective in inhibiting Aβ-peptide production, and apharmaceutically acceptable carrier.
 15. A pharmaceutical compositionfor treating a disease or a condition selected from the group consistingof Alzheimer's disease, hereditary cerebral hemorrhage with amyloidosis,cerebral amyloid angiopathy, a prion-mediated disease, inclusion bodymyositis, stroke, multiple sclerosis and Down's Syndrome in a mammal,comprising an amount of the compound according to claim 1 or apharmaceutically acceptable salt thereof, that is effective in treatingsuch disease or condition, and a pharmaceutically acceptable carrier.16. A method of inhibiting Aβ-peptide production in a mammal, comprisingadministering to said mammal an amount of the compound according toclaim 1 or a pharmaceutically acceptable salt thereof, that is effectivein inhibiting Aβ-production.
 17. A method of treating a disease orcondition selected from the group consisting of Alzheimer's disease,hereditary cerebral hemorrhage with amyloidosis, cerebral amyloidangiopathy, a prion-mediated disease, inclusion body myositis, stroke,multiple sclerosis and Down's Syndrome in a mammal, comprisingadministering to said mammal an amount of the compound according toclaim 1 or a pharmaceutically acceptable salt thereof, that is effectivein inhibiting Aβ-production.
 18. A method of treating a disease orcondition selected from the group consisting of Alzheimer's disease,hereditary cerebral hemorrhage with amyloidosis, cerebral amyloidangiopathy, a prion-mediated disease, inclusion body myositis, stroke,multiple sclerosis and Down's Syndrome in a mammal, comprisingadministering to said mammal an amount of the compound according toclaim 1 or a pharmaceutically acceptable salt thereof, that is effectivein treating such condition.
 19. A pharmaceutical composition fortreating a disease or condition associated with Aβ-peptide production ina mammal, comprising (a) the compound according to claim 1 or apharmaceutically acceptable salt thereof; (b) an active agent selectedfrom the group consisting of a memory enhancement agent, antidepressant,anxiolytic, antipsychotic agent, sleep disorder agent, anti-inflammatoryagent, anti-oxidant agent, cholesterol modulating agent andanti-hypertensive agent; and (c) a pharmaceutically acceptable carrier;wherein (a) and (b) are present in amounts that render the compositioneffective in treating such disease or condition.
 20. A pharmaceuticalcomposition for treating a disease or condition selected from the groupconsisting of Alzheimer's disease, hereditary cerebral hemorrhage withamyloidosis, cerebral amyloid angiopathy, a prion-mediated disease,inclusion body myositis, stroke, multiple sclerosis and Down's Syndrome,in a mammal, comprising (a) the compound according to claim 1 or apharmaceutically acceptable salt thereof; (b) an active agent selectedfrom the group consisting of a memory enhancement agent, antidepressant,anxiolytic, antipsychotic agent, sleep disorder agent, anti-inflammatoryagent, anti-oxidant agent, cholesterol modulating agent andanti-hypertensive agent; and (c) a pharmaceutically acceptable carrier;wherein (a) and (b) are present in amounts that render the compositioneffective in treating such disease or condition.
 21. A method oftreating a disease or condition associated with Aβ-peptide production ina mammal, comprising administering to said mammal (a) the compoundaccording to claim 1 or a pharmaceutically acceptable salt thereof; and(b) an active agent selected from the group consisting of a memoryenhancement agent, antidepressant, anxiolytic, antipsychotic agent,sleep disorder agent, anti-inflammatory agent, anti-oxidant agent,cholesterol modulating agent and anti-hypertensive agent; wherein (a)and (b) are present in amounts that render the composition effective intreating such disease or condition.
 22. A method of treating a diseaseor condition selected from the group consisting of Alzheimer's disease,hereditary cerebral hemorrhage with amyloidosis, cerebral amyloidangiopathy, a prion-mediated disease, inclusion body myositis, stroke,multiple sclerosis and Down's Syndrome, in a mammal, comprisingadministering to said mammal (a) the compound according to claim 1 or apharmaceutically acceptable salt thereof; and (b) an active agentselected form the group consisting of a memory enhancement agent,antidepressant, anxiolytic, antipsychotic agent, sleep disorder agent,anti-inflammatory agent, anti-oxidant agent, cholesterol modulatingagent and anti-hypertensive agent; wherein (a) and (b) are present inamounts that render the composition effective in treating such diseaseor condition.